Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine d3 receptor

ABSTRACT

The present invention relates to novel acylaminocycloalkyl compounds, in particular to the compounds of the formula I as described herein and to their salts and N-oxides. The compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the dopamine D3 receptor. 
     
       
         
         
             
             
         
       
     
     In formula I, the variables have the following meanings:
     m is 1 or 2,   n is 1 or 2,   A is selected from the group consisting of CH 2 , CH 2 CH 2 , CHFCH 2  and CF 2 CH 2 ,   R 1  is an oxygen containing cyclic radical selected such as C 3 -C 6  cycloalkyl, which carries one or two oxygen containing radicals selected from the group consisting of OH, C 1 -C 2 -alkoxy, fluorinated C 1 -C 2 -alkoxy, and a carbonyl oxygen,   R 2  is selected from the group consisting of hydrogen, OH and fluorine,   R 3a  is selected from the group consisting of hydrogen and methyl,   R 3b  is selected from the group consisting of hydrogen and methyl,   R 4  is branched C 4 -C 6  alkyl or branched fluorinated C 4 -C 6  alkyl, and   R 5  is inter alia C 1 -C 6  alkyl, fluorinated C 1 -C 3  alkyl, C 1 -C 2 -alkoxy-C 1 -C 4 -alkyl, fluorinated C 1 -C 2 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, fluorinated hydroxy-C 1 -C 4 -alkyl, oxetanyl, fluorinated oxetanyl, oxolanyl, fluorinated oxolanyl, C 3 -C 5  cycloalkyl, fluorinated C 3 -C 5  cycloalkyl, etc.

CROSS-REFERENCE TO RELATED APPLICATIONS

This claims priority to U.S. Patent Application No. 61/786,869, filed onMar. 15, 2013, and U.S. Patent Application No. 61/918,524, filed on Dec.19, 2013, the entire contents of all of which are fully incorporatedherein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to novel acylaminocycloalkyl compounds, inparticular to the compounds of the formula I as described herein. Thecompounds possess valuable therapeutic properties and are suitable, inparticular, for treating diseases that respond to modulation of thedopamine D3 receptor.

Neurons obtain their information by way of G protein-coupled receptors,inter alia. A large number of substances exert their effect by way ofthese receptors. One of them is dopamine. Confirmed findings exist withregard to the presence of dopamine and its physiological function as aneurotransmitter. Disorders in the dopaminergic transmitter systemresult in diseases of the central nervous system which include, forexample, schizophrenia, bipolar disorders, depression, Parkinson'sdisease, disorders associated with drug abuse. These diseases, andothers, are treated with drugs which interact with the dopaminereceptors.

Up until 1990, two subtypes of dopamine receptor had been clearlydefined pharmacologically, termed D1 and D2 receptors. More recently, athird subtype was found, namely, the D3 receptor which appears tomediate some effects of antipsychotics and antiparkinsonian drugs (J. C.Schwartz et al., “The Dopamine D₃ Receptor as a Target forAntipsychotics” in Novel Antipsychotic Drugs, H. Y. Meltzer, ed., RavenPress, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging1998, 12:495-514; J. N. Joyce, Pharmacology and Therapeutics 2001,90:231-59, “The Dopamine D3 Receptor as a Therapeutic Target forAntipsychotic and Antiparkinsonian Drugs”). Since then, the dopaminereceptors have been divided into two families. On the one hand, there isthe D2 group, consisting of D2, D3 and D4 receptors, and, on the otherhand, the D1 group, consisting of D1 and D5 receptors.

Whereas D1 and D2 receptors are widely distributed, D3 receptors appearto be expressed regioselectively. Thus, these receptors arepreferentially to be found in the limbic system and the projectionregions of the mesolimbic dopamine system, especially in the nucleusaccumbens, but also in other regions, such as the amygdala. Because ofthis comparatively regioselective expression, D3 receptors are regardedas being a target having few side-effects and it is assumed that while aselective D3 ligand would have the properties of known antipsychotics,it would not have their dopamine D2 receptor-mediated neurologicalside-effects (P. Sokoloff et al., Arzneim. Forsch./Drug Res. 42(1):224(1992), “Localization and Function of the D₃ Dopamine Receptor”; P.Sokoloff et al., Nature, 347:146 (1990), “Molecular Cloning andCharacterization of a Novel Dopamine Receptor (D3) as a Target forNeuroleptics”).

Selective Dopamine D3 receptor ligands have been suggested for thetreatment of Parkinson's disease, schizophrenia, depression, motivationdisturbances (amotivation) (see J. N. Joyce, Pharmacology andTherapeutics 90, 2001, 231-259; B. Levant, CNS Drugs 1999, 12, 391), forthe treatment cognitive dysfunction, in particular cognitive dysfunctionassociated with schizophrenia or dementia (see J. Laszy et al.,Psychopharmacology, 2005, 179, 567-575), for the treatment ofdisturbances associated with substance abuse, i.e. for the treatment ofdrug addiction or drug dependence (see J. N. Joyce, loc. cit. and C. A.Heidbreder, Brain Research Reviews 49, 2005, 77-105), for the treatmentof anxiety (see Z. Rogoz et al., Polish Journal of Pharmacology, 2003,55, 449-454), for the treatment of pain (see Levant et al., Neurosci.Lett. 2001, 303, 9), for the treatment of renal function disorders (seeB. Mühlbauer, E. Müster, G. Luippold, Acta Physiologica Scandinavica,2000, 168 (1), 219-223), for the treatment of eating disorders (see S.C. Benoit, J. A. McQuade, D. J. Clegg, M. Xu, P. A. Rushing, S. C.Woods, R. J. Seeley, J. Randy, Behavioral Neuroscience, 2003, 117(1),46-54) and for the treatment of dyskinesia, especiallyL-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia (LID) (seeNaomi P. Visanji, Susan H. Fox, Tom Johnston, Gabriela Reyes, Mark J.Millan, Jonathan M. Brotchie, Neurobiology of Disease 35 (2009),184-192).

WO 2006/082456 describes cyclohexylamides, which are Dopamine D3, D2 and5HT1A antagonists. The cycloalkyl moiety of the compounds of WO2006/082456 carries an alkylene-N-piperazinyl radical, where the othernitrogen carries a phenyl radical having a fused saturated carbocyclicradical.

Similar compounds are also known from WO 2007/148208, where the fusedcarbobicyclic radical is replaced by unsubstituted or substituted arylor hetaryl and where the acyl group requires to be substituted.

Similar compounds are also known from US2009/143398, where thecarbobicyclic radical is replaced by a 5,6-dichloro-2-amino-4-pyrimidylradical.

Similar compounds are also known from WO 2011/161009 and WO 2012/004206,where the carbobicyclic radical is replaced by a 5,6-disubstituted2-pyridyl radical having a fused heterocycle.

Compounds having a heteroaromatic ring, which is bound via a linker to apiperazine radical carrying a 1-(4-pyrimidinyl)-piperazinyl radicalreceptor have been described previously in WO 2004/080981,WO2004/108706, WO 2005/118558, WO 2005/118571, WO 2006/015842 and WO2009/056625. The compounds possess high affinities for the dopamine D₃receptor, and have therefore been proposed as being suitable fortreating diseases of the central nervous system.

Although some of the compounds of prior art are known to have highaffinities for the Dopamine D3 receptor of less than 10 nM, there isstill an ongoing need for compounds which selectively bind to theDopamine D3 receptor. In particular, there is an ongoing need forcompounds which have one of the following characteristics:

-   -   i. Selective binding to the Dopamine D3 receptor, in particular        vis-à-vis binding to the Dopamine D2 receptor, adrenergic        receptors such as alpha-1 or alpha-2 receptors or serotonine        type receptors such as serotoninergic 5HT1 and 5HT2 receptors;    -   ii. metabolic stability, in particular microsomal stability,        e.g. measured in vitro, in liver microsomes from various species        (e.g. rat or human) in human cells, such as hepatocytes;    -   iii. no or only low inhibition of cytochrome P450 (CYP) enzymes:        cytochrome P450 (CYP) is the name for a superfamily of heme        proteins having enzy-matic activity (oxidase). They are also        particularly important for the degradation (metabolism) of        foreign substances such as drugs or xenobiotics in mammalian        organisms. The principal representatives of the types and        subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6        and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice,        cimetidine, erythro-mycin) are used at the same time as        medicinal substances which are degraded by this enzyme system        and thus compete for the same binding site on the enzyme, the        degradation thereof may be slowed down and thus effects and side        effects of the administered medicinal substance may be        undesirably enhanced;    -   iv. a suitable solubility in water (in mg/ml);    -   v. suitable pharmacokinetics (time course of the concentration        of the compound of the invention in plasma or in tissue, for        example brain). The pharmacokinetics can be described by the        following parameters: half-life, volume of distribution (in        l·kg⁻¹), plasma clearance (in l·h⁻¹·kg⁻¹), AUC (area under the        curve, area under the concentration-time curve (in ng·h·l⁻¹),        oral bioavailability, (the dose-normalized ratio of AUC after        oral administration and AUC after intravenous administration),        the so-called brain-plasma ratio (the ratio of AUC in brain        tissue and AUC in plasma);    -   vi. no or only low blockade of the hERG channel: compounds which        block the hERG channel may cause a prolongation of the QT        interval and thus lead to serious disturbances of cardiac rhythm        (for example so-called “torsade de pointes”). The potential of        compounds to block the hERG channel can be determined by means        of the displacement assay with radiolabelled dofetilide which is        described in the literature (G. J. Diaz et al., Journal of        Pharmacological and Toxicological Methods, 50 (2004), 187-199).        A smaller IC50 in this dofetilide assay means a greater        probability of potent hERG blockade. In addition, the blockade        of the hERG channel can be measured by electro-physiological        experiments on cells which have been transfected with the hERG        channel, by so-called whole-cell patch clamping (G. J. Diaz et        al., Journal of Pharmacological and Toxicological Methods, 50        (2004), 187-199);    -   vii. high free fraction in brain, i.e. the fraction of the        compound bound to proteins should be low;    -   viii. low lipophilicity.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is thus based on the object of providing compoundswhich selectively bind to the dopamine D3 receptor at lowconcentrations.

The compounds are further intended to display at least one of theproperties i. to viii. mentioned above, in particular high selectivitywith regard to dopamine D3 receptor vs. dopamine D2 receptor, enhancedmetabolic stability, in particular microsomal stability, cytosolicstability or hepatocyte stability, low affinity to the HERG receptor,low inhibition of cytochrome P450 (CYP) enzymes, suitable solubility inwater and suitable pharmacokinetics.

This object and further objects are achieved by the compounds of thegeneral formula I described below, the N-oxides and the pharmaceuticallysuitable salts thereof:

where

-   m is 1 or 2,-   n is 1 or 2,-   A is selected from the group consisting of CH₂, CH₂CH₂, CHFCH₂ and    CF₂CH₂,-   R¹ is an oxygen containing cyclic radical selected from oxetanyl,    fluorinated oxetanyl, oxolanyl, fluorinated oxolanyl, C₃-C₆    cycloalkyl, which carries one or two oxygen containing radical    selected from the group consisting of OH, C₁-C₂-alkoxy, fluorinated    C₁-C₂-alkoxy, and a carbonyl oxygen, and which may additionally    carry 1 or 2 radicals selected from fluorine, C₁-C₂-alkyl and    fluorinated C₁-C₂-alkyl;-   R² is selected from the group consisting of hydrogen and fluorine,-   R^(3a) is selected from the group consisting of hydrogen and methyl,-   R^(3b) is selected from the group consisting of hydrogen and methyl,-   R⁴ is branched C₄-C₆ alkyl or branched fluorinated C₄-C₆ alkyl, and-   R⁵ is selected from the group consisting of C₁-C₆ alkyl, fluorinated    C₁-C₃ alkyl, C₁-C₂-alkoxy-C₁-C₄-alkyl, fluorinated    C₁-C₂-alkoxy-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, fluorinated    hydroxy-C₁-C₄-alkyl, oxetanyl, fluorinated oxetanyl, oxolanyl,    fluorinated oxolanyl, C₃-C₅ cycloalkyl, fluorinated C₃-C₅    cycloalkyl, C₃-C₅ cycloalkyl-C₁-C₄-alkyl, fluorinated C₃-C₅    cycloalkyl-C₁-C₄-alkyl, C₃-C₅ cycloalkoxy-C₁-C₄-alkyl and    fluorinated C₃-C₅ cycloalkoxy-C₁-C₄-alkyl, where the cycloalkyl    moiety in the last six mentioned groups of radicals may carry 1 or 2    radicals selected from hydroxyl, C₁-C₂-alkoxy, fluorinated    C₁-C₂-alkoxy, C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl, where the    cycloalkoxy moiety in the last two mentioned radicals may carry 1 or    2 radicals selected from hydroxyl, C₁-C₂-alkoxy, fluorinated    C₁-C₂-alkoxy, C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl.

The present invention therefore relates to the compounds of the generalformula I, the N-oxides and the pharmaceutically acceptable salts of thecompounds of formula I, the prodrugs of the compounds of formula I andthe pharmaceutically acceptable salts of said N-oxides and prodrugs ofthe compounds of formula I. The present invention in particular relatesto the compounds of the general formula I and to their pharmaceuticallyacceptable salts.

The present invention therefore relates to the compounds of the generalformula I, the N-oxides and the pharmaceutically acceptable salts of thecompounds of formula I, the prodrugs of the compounds of formula I andthe pharmaceutically acceptable salts of said N-oxides and prodrugs ofthe compounds of formula I for the use as a medicament.

The present invention also relates to the compounds of the generalformula I, the N-oxides, the pharmaceutically acceptable salts of thecompounds of formula I, the prodrugs of the compounds of formula I andthe pharmaceutically acceptable salts of said N-oxides or prodrugs ofthe compounds of formula I for the use in the treatment of a medicaldisorder susceptible to treatment with a dopamine D3 receptor ligand, inparticular from a disorder selected from neurological and psychiatricdisorders which can be treated by modulation of the dopamine D₃receptor, in particular by at least partially antagonizing the dopamineD3 receptor.

The compounds of the formula I, their pharmaceutically acceptable salts,their N-oxides and their prodrugs, and the pharmaceutically acceptablesalts of said N-oxides or prodrugs selectively bind to the dopamine D₃receptor even at low concentrations, and are in particular at leastpartial antagonists of the D3 receptor.

They are additionally distinguished by a high selectivity in relation tobinding to the dopamine D3 receptor vis-à-vis binding to dopamine D2receptor or adrenergic or serotonergic receptors such as alpha-1,alpha-2, 5HT1 and 5HT2. The compounds of the invention may additionallyhave one or more of the above mentioned properties ii. to viii.

The compounds of the formula I, their pharmaceutically acceptable salts,their N-oxides, their prodrugs, and the pharmaceutically acceptablesalts of said N-oxides, and prodrugs are therefore particularly suitablefor treating disorders and conditions in creatures, especially humancreatures, which can be treated or controlled by modulation of thedopamine D3 receptor.

The diseases which respond to the influence of dopamine D3 receptorligands or agonists include disorders and diseases of the centralnervous system, in particular affective disturbances, neuroticdisturbances, stress disturbances and somatoform disturbances andpsychoses, and especially Parkinson's disease, schizophrenia, majordepressive disorder (depression), motivation disturbances, bipolardisorder, disorders related to substance abuse (also termed drug abuse),eating disorders, cognitive dysfunction, in particular cognitivedysfunction associated with schizophrenia or dementia, anxiety,attention deficit disorder with or without hyperactivity, personalitydisorder and dyskinesia, in particular L-DOPA induced dyskinesia (LID).In addition, D3-mediated diseases may include disturbances of kidneyfunction, i.e. renal function disorders, in particular kidney functiondisturbances which are caused by diabetes such as diabetes mellitus,also termed as diabetic nephropathy. It may also be possible toameliorate pain by administering dopamine D3 receptor ligands.

The invention therefore also relates to the use of the compounds of theformula I, their N-oxides, prodrugs and their pharmaceuticallyacceptable salts and the pharmaceutically acceptable salts of saidN-oxides or prodrugs, for the manufacture of a medicament, in particularof a medicament which is suitable for the treatment of a disorder or acondition which can be treated by modulation of the dopamine D3receptor.

The invention further relates to a medicament, in particular amedicament which is suitable for the treatment of a disorder or acondition which can be treated by modulation of the dopamine D3 receptorand in particular by at least partially antagonizing the dopamine D3receptor. The medicament comprises at least one compound of the formulaI, as described herein, or an N-oxide, or a prodrug of said compound I,or a pharmaceutically acceptable salt of the compound of the formula Ior a pharmaceutically acceptable salt of the N-oxide, or the prodrug ofcompound of the formula I.

DETAILED DESCRIPTION OF THE INVENTION

The terms “compound of the formula I” and “compounds I” are used assynonyms.

The term “prodrugs” means compounds which are metabolized in vivo to thecompounds I of the invention. Typical examples of prodrugs are describedin C. G. Wermuth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. These include for examplephosphates, carbamates, amino acids, esters, amides, peptides, ureas andthe like. Suitable prodrugs in the present case may be for examplederivatives of those compounds I carrying an OH group, where the OHgroup forms an ester linkage, i.e. where the hydrogen atom of the OHgroup is substituted by a C₁-C₄-alkylcarbonyl group, e.g. by acetyl,propionyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl ortert-butylcarbonyl (pivaloyl), by benzoyl, or by an acyl group derivedfrom an amino acid, e.g. glycine, alanine, serine, phenylalanine and thelike, which is linked to the oxygen or nitrogen of the OH group via thecarbonyl group of the amino acid. Further suitable prodrugs arealkylcarbonyloxyalkyl carbonates of compounds I carrying an OH group inwhich the hydrogen atom of the OH group has been replaced by a group ofthe formula —C(═O)—O—CHR^(p)—O—C(═O)—R^(q) in which R^(p) and R^(q) areindependently of one another C₁-C₄-alkyl. Such carbonates are describedfor example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J.Medicinal Chem. 1988, 31(2), 318-322. These groups can then beeliminated under metabolic conditions and result in compounds I.Therefore, said prodrugs and their pharmaceutically acceptable salts arealso part of the invention.

The term “pharmaceutically acceptable salts” refers to cationic oranionic salts compounds, wherein the counter ion is derived frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids.

As the compound of formula I or its prodrug, or N-oxide is basic, saltsmay be prepared from pharmaceutically acceptable non-toxic acids,including inorganic and organic acids. Such acids include acetic,trifluoroacetic acid, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of formula I are meant to also include thepharmaceutically acceptable salts.

The compounds of the invention may be in the form of a mixture ofdiastereomers, or of a mixture of diastereomers in which one of the twodiastereomers is enriched, or of essentially diastereomerically purecompounds (diastereomeric excess de >90%). The compounds are preferablyin the form of essentially diastereomerically pure compounds(diastereomeric excess de >90%). The compounds I of the invention mayfurthermore be in the form of a mixture of enantiomers (for example asracemate), of a mixture of enantiomers in which one of the twoenantiomers is enriched, or essentially in enantiomerically purecompounds (enantiomeric excess ee >90%). It is preferred to employ thecompounds enantiomerically pure or diastereomerically pure.

The present invention moreover relates to compounds as defined herein,wherein one or more of the atoms depicted in formula I have beenreplaced by a stable isotope (e.g., hydrogen by deuterium, ¹²C by ¹³C,¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) or by an instable isotope (e.g. ¹²C by ¹¹C, ¹⁶Oby ¹⁵O, ¹⁹F, by ¹⁸F), preferably by a stable isotope, or enriched withregard to said isotope beyond the natural level. Of course, thecompounds according to the invention contain more of the respectiveisotope than this naturally occurs and thus is anyway present in thecompounds I.

The compounds of the formula I and their salts in the solid form mayexist in more than one crystal structure (polymorphism), and may also bein the form of hydrates or other solvates. The present inventionincludes any polymorph of the compound I or its salt as well as anyhydrate or other solvate.

In the context of the present description, unless stated otherwise, theterms “alkyl”, “fluorinated alkyl”, “alkoxy”, “fluorinated alkoxy” andradicals derived therefrom, such as “hydroxyalkyl”, “alkoxyalkyl”,“fluorinated hydroxyalkyl” and “fluorinated alkoxyalkyl”, representgroups of individual radicals. The groups of noncyclic radicals “alkyl”,“alkoxy”, “fluorinated alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”,“fluorinated hydroxyalkyl” and “fluorinated alkoxyalkyl”, always includeboth unbranched and branched “alkyl”, “alkoxy”, “fluorinated alkoxy”,“hydroxyalkyl”, “alkoxyalkyl”, “fluorinated hydroxyalkyl” and“fluorinated alkoxyalkyl”, respectively.

The prefix C_(n)-C_(m)- indicates the respective number of carbons inthe hydrocarbon unit. Unless indicated otherwise, fluorinatedsubstituents usually have 1, 2, 3, 4, 5, 6 or 7 fluorine atoms.

Examples of meanings are:

Alkyl, and the alkyl moieties for example in alkoxy, alkoxyalkyl andhydroxyalkyl: saturated, straight-chain or branched hydrocarbon radicalshaving one or more C atoms, e.g. 1, 2, 3, 4, 5 or 6 carbon atoms.Examples of C₁-C₃-alkyl are methyl, ethyl, n-propyl and 1-methylethyl.

Branched C₄-C₆ alkyl is a branched alkyl radical having 4, 5 or 6 carbonatoms. Examples of branched C₄-C₆-alkyl are 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl (=tert.-butyl), 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl.

Fluorinated alkyl and the alkyl moieties for example in fluorinatedalkoxy, fluorinated alkoxyalkyl and fluorinated hydroxyalkyl: saturated,straight-chain or branched hydrocarbon radicals having one or more Catoms, e.g. 1, 2, 3, 4, 5 or 6 carbon atoms, in particular 1 or 2 carbonatoms, where at least one of the hydrogen atoms of the hydrocarbonradical has been replaced by a fluorine atom, examples includingfluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl,1,1-difluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl etc.

Branched fluorinated C₄-C₆ alkyl is a branched alkyl radical having 4, 5or 6 carbon atoms, as defined above, where at least one of the hydrogenatoms of the branched alkyl radical has been replaced by a fluorineatom, examples including 1-(fluoromethyl)ethyl, 1-(difluoromethyl)ethyl,1-(trifluoromethyl)ethyl, 1,1,1,3,3,3-hexafluoro-2-propyl,heptafluoro-2-propyl, 1-(fluoromethyl)-1-propyl,1-(difluoromethyl)-1-propyl, 1-(trifluoromethyl)-1-propyl,2-(fluoromethyl)-2-propyl, 2-(difluoromethyl)-2-propyl and2-(trifluoromethyl)-2-propyl.

C₁-C₂-alkoxy is methoxy and ethoxy.

C₁-C₂-alkoxy-C₁-C₂-alkyl is methoxymethyl, ethoxymethyl, 1-methoxyethyl,2-methoxyethyl, 1-ethoxyethyl and 2-methoxyethyl.

C₁-C₂-alkoxy-C₁-C₄-alkyl: C₁-C₂-alkoxyC₁-C₂-alkyl as mentioned above andalso, for example 2-(methoxy)propyl, 2-(ethoxy)propyl,3-(methoxy)propyl, 3-(ethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,3-(methoxy)butyl, 3-(ethoxy)butyl, 4-(methoxy)butyl and 4-(ethoxy)butyl.

Hydroxyalkyl: an alkyl radical ordinarily having 1, 2, 3 or 4 C atoms,in which one hydrogen atom is replaced by an OH radical. Examplesthereof are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,1-hydroxypropyl, 2-hydroxypropyl, 1-methyl-1-hydroxyethyl,1-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 1-methyl-2-hydroxypropyl,1,1-dimethyl-2-hydroxyetyl, 1-methyl-1-hydroxypropyl etc.

Fluorinated alkoxy is an alkoxy radical as described above, in which thehydrogen atoms of these groups are partly or completely replaced byfluorine atoms, i.e. for example fluorinated C₁-C₂-alkoxy, such asfluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-terafluoroethoxy andpentafluoro-ethoxy.

Fluorinated alkoxyalkyl is an alkoxyalkyl radical as described above, inwhich the hydrogen atoms of the alkoxy part and/or of the alkyl part arepartly or completely replaced by fluorine atoms, i.e. for examplefluorinated C₁-C₂-alkoxy-C₁-C₂-alkyl-, such as fluoromethoxymethyl,difluoromethoxymethyl, trifluoromethoxymethyl, 2-fluoroethoxymethyl,2,2-difluoromethoxymethyl, 2,2,2-trifluoroethoxymethyl,1,1,2,2-terafluoroethoxymethyl, pentafluoroethoxymethyl,1-(fluoromethoxy)ethyl, 1-(difluoromethoxy)ethyl,1-(trifluoromethoxy)ethyl, 1-(2-fluoroethoxy)ethyl,1-(2,2-difluoroethoxy)ethyl, 1-(2,2,2-trifluoroethoxy)ethyl,1-(1,1,2,2-terafluoroethoxy)ethyl, 1-(pentafluoroethoxy)ethyl,2-(fluoromethoxy)ethyl, 2-(difluoromethoxy)ethyl,2-(trifluoromethoxy)ethyl, 2-(2-fluoroethoxy)ethyl,2-(2,2-difluoroethoxy)ethyl, 2-(2,2,2-trifluoroethoxy)ethyl,2-(1,1,2,2-terafluoroethoxy)ethyl, 2-(pentafluoroethoxy)ethyl,methoxyfluoroethyl, ethoxyfluoro-methyl, methoxydifluoromethyl,ethoxydifluoromethyl, difluoromethoxyfluoroethyl,2,2,2-trifluoroethoxyfluoromethyl, difluoromethoxydifluoromethyl,2,2,2-trifluoroethoxydifluoromethyl, 2-methoxy-1-fluoroethyl,2-ethoxy-1-fluoroethyl, 2-difluoromethoxy-1-fluoroethyl,2-(2,2-difluoroethoxy)-1-fluoroethyl,2-(2,2,2-trifluoroethoxy)-1-fluoroethyl, 2-methoxy-1,1-difluoroethyl,2-ethoxy-1,1-difluoroethyl, 2-difluoromethoxy-1,1-difluoroethyl,2-(2,2-difluoroethoxy)-1,1-difluoroethyl and2-(2,2,2-trifluoroethoxy)-1,1-difluoroethyl. Examples of fluorinatedC₁-C₂-alkoxy-C₁-C₄-alkyl are fluorinated C₁-C₂-alkoxy-C₁-C₂-alkyl asdefined above and also for example 3-(fluoromethoxy)propyl,3-(difluoromethoxy)propyl, 3-(trifluoromethoxy)propyl,3-(2-fluoroethoxy)propyl, 3-(2,2-difluoroethoxy)propyl,3-(2,2,2-trifluoroethoxy)propyl, 3-(1,1,2,2-terafluoroethoxy)propyl,3-(pentafluoro-ethoxy)propyl, 2-fluoro-3-methoxypropyl,2-fluoro-3-ethoxypropyl, 2,2-difluoro-3-methoxypropyl,3-difluoromethoxy-2,2-difluoropropyl, 2-fluoro-3-(fluoromethoxy)propyl,4-(fluoromethoxy)butyl, 4-(difluoromethoxy)butyl,4-(trifluoromethoxy)butyl, 4-(2-fluoroethoxy)butyl,4-(2,2-difluoroethoxy)butyl, 4-(2,2,2-trifluoroethoxy)butyl,4-(1,1,2,2-terafluoroethoxy)butyl, 4-(pentafluoro-ethoxy)butyl,1-fluoro-4-methoxybutyl, 2-fluoro-4-methoxybutyl,3-fluoro-4-methoxybutyl, 2-fluoro-3-ethoxypropyl,2-fluoro-3-fluoromethoxy-2-methyl-butyl, 2,2-difluoro-3-methoxybutyl,4-difluoromethoxy-2,2-difluorobutyl, 2-fluoro-4-(fluoromethoxy)butyl.

C₃-C₆ cycloalkyl is a cycloaliphatic radical having 3, 4, 5 or 6 carbonatoms as ring members, while C₃-C₅ cycloalkyl is a cycloaliphaticradical having 3, 4 or 5 carbon atoms as ring members, examplesincluding cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Fluorinated C₃-C₅ cycloalkyl is a C₃-C₅ cycloalkyl radical as definedabove, in which the hydrogen atoms of the cycloalkoxy part and/or of thealkyl part are partly or completely replaced by fluorine atoms, examplesincluding 1-fluorocyclopropyl, 2-fluorocyclopropyl,2,2-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl,2,2-difluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl,1-fluorocyclopentyl, 2-fluorocyclopentyl, 3-fluorocyclopentyl,2,2-difluorocyclopentyl, 2,3-difluorocyclopentyl, etc.

C₃-C₅ cycloalkyl-C₁-C₄-alkyl is a C₁-C₄-alkyl radical as defined above,where one hydrogen atom is replaced by a cycloalkyl radical, examplesincluding cyclopropylme-thyl, cyclobutylmethyl, 1-cyclopropylethyl,2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethylcyclopentylmethyl, 1-cyclopentylethyl and 2-cyclopentylethyl.

Fluorinated C₃-C₅ cycloalkyl-C₁-C₄-alkyl is a C₃-C₅cycloalkoxy-C₁-C₄-alkyl radical as defined above, in which the hydrogenatoms of the cycloalkyl part and/or of the alkyl part are partly orcompletely replaced by fluorine atoms.

C₃-C₅ cycloalkoxy-C₁-C₄-alkyl is a C₁-C₄-alkyl radical as defined above,where one hydrogen atom is replaced by a cycloalkoxy radical such ascyclopropyloxy, cyclo-butyloxy or cyclopentyloxy, examples includingcyclopropoxymethyl, cyclobutoxyme-thyl, 1-cyclopropoxyethyl,2-cyclopropoxyethyl, 1-cyclobutoxyethyl, 2-cyclobutoxyethylcyclopentoxymethyl, 1-cyclopentoxyethyl and 2-cyclopentoxyethyl.

Fluorinated C₃-C₅ cycloalkoxy-C₁-C₄-alkyl is a C₃-C₅cycloalkoxy-C₁-C₄-alkyl radical as defined above, in which the hydrogenatoms of the cycloalkoxy part and/or of the alkyl part are partly orcompletely replaced by fluorine atoms.

Examples of oxetanyl include 2-oxetanyl and 3-oxetanyl. Fluorinatedoxetanyl includes e.g. 2-fluoro-2-oxethanyl, 3-fluoro-2-oxetanyl,3,3-difluoro-2-oxetanyl, 2-fluorooxetan-3-yl, 3-fluorooxetan-3-yl and2,2-difluorooxetan-3-yl.

Examples of oxolanyl include 2-oxolanyl and 3-oxolanyl. Fluorinatedoxolanyl includes e.g. 2-fluoro-2-oxolanyl, 3-fluoro-2-oxolanyl,4-fluoro-2-oxolanyl, 5-fluoro-2-oxolanyl, 2-fluoro-3-oxolanyl,3-fluoro-3-oxolanyl, 4-fluoro-3-oxolanyl, 5-fluoro-3-oxolanyl,3,3-difluoro-2-oxolanyl, 4,4-difluoro-2-oxolanyl,5,5-difluoro-2-oxolanyl, 2,2-difluoro-3-oxolanyl,4,4-difluoro-3-oxolanyl and 5,5-difluoro-3-oxolanyl.

In relation to their intended use, the variables m, n, A, R¹, R²,R^(3a), R^(3b), R⁴ and R⁵ in formula I in particular have the followingmeanings, where these represent, both considered on their own and incombination with at least one other or all, special embodiments of thecompounds of the formula I:

In a first group of particular embodiments, R¹ in formula I is selectedfrom the group consisting of C₃-C₆ cycloalkyl, which carries one oxygencontaining radical selected from the group consisting of OH, methoxy,and a carbonyl oxygen, and which may additionally carry 1 radicalselected from fluorine, C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl. Moreparticularly, R¹ is selected from the group consisting of C₃-C₆cycloalkyl, which carries one hydroxyl group, and which may additionallycarry 1 radical selected from fluorine, C₁-C₂-alkyl and fluorinatedC₁-C₂-alkyl. Particularly preferred examples of R¹ include1-hydroxycyclopropyl, 2-hydroxycyclopropyl, 1-hydroxycyclobutyl,2-hydroxycyclobutyl, 3-hydroxycyclobutyl,3-hydroxy-3-(trifluoromethyl)-cyclobutyl, 2-oxocyclobutyl,3-hydroxycyclopentyl, 2-hydroxycyclopentyl, 3-hydroxycyclohexyl,4-hydroxycyclohexyl, 4-methoxycyclohexyl and 4-oxocyclohexyl. EspeciallyR¹ is cis- or trans-3-hydroxycyclobutyl, cis- ortrans-3-hydroxycyclopentyl, cis- or trans-3-hydroxycyclohexyl or cis- ortrans-4-hydroxycyclohexyl. In a very special group of embodiments, R¹ istrans-4-hydroxycyclohexyl. In another very special group of embodimentsR¹ is cis-4-hydroxycyclohexyl. In a further very special group ofembodiments, R¹ is trans-3-hydroxycyclobutyl. In yet a further veryspecial group of embodiments R¹ is cis-3-hydroxycyclobutyl.

In a second group of particular embodiments, R¹ in formula I is selectedfrom the group consisting of oxetanyl and oxolanyl. More particularly,R¹ is selected from the group consisting of 2-oxetanyl and 3-oxetanyl.

R² is in particular hydrogen.

In a particular group of embodiments, the variable m in formula I is 2.

In another particular group of embodiments, the variable m in formula Iis 1.

In a particular group of embodiments, the variable n in formula I is 2.

In a special group of embodiments, the both variables m and n in formulaI are 2.

In another special group of embodiments, the both variables m and n informula I are 1.

In another special group of embodiments, the variable m in formula I is2 while the variable n is 1.

In particular groups of embodiments of the invention, both R^(3a) andR^(3b) are hydrogen or one of R^(3a) and R^(3b) is methyl, while theother is hydrogen.

In a special group of embodiments of the invention, both R^(3a) andR^(3b) in formula I are hydrogen.

In another special groups of embodiments of the invention one of R^(3a)and R^(3b) in formula I is methyl, while the other is hydrogen.

If R^(3a) is methyl, the carbon atom bearing the radical R^(3a) is anasymmetric centre and thus said carbon atom may adopt eitherS-configuration or R-configuration. The invention thus relates both tothe essentially pure R-enantiomer (enantiomeric excess ee >90%), i.e. tothe compounds of formula I, where R^(3a) is methyl and the carbon atombearing the radical R^(3a) has R-configuration, and to the essentiallypure S-enantiomer (enantiomeric excess ee >90%), i.e. to the compoundsof formula I, where R^(3a) is methyl and the carbon atom bearing theradical R^(3a) has S-configuration. The invention also relates toracemic mixtures of said R-enantiomer and said S-enantiomer as well asto non-racemic mixtures, which are enriched with regard to either saidR-enantiomer or said S-enantiomer.

Likewise, if R^(3b) is methyl, the carbon atom bearing the radicalR^(3b) is an asymmetric centre and thus said carbon atom may adopteither S-configuration or R-configuration. The invention thus relatesboth to the essentially pure R-enantiomer (enantiomeric excess ee >90%),i.e. to the compounds of formula I, where R^(3b) is methyl and thecarbon atom bearing the radical R^(3b) has R-configuration, and to theessentially pure S-enantiomer (enantiomeric excess ee >90%), i.e. to thecompounds of formula I, where R^(3b) is methyl and the carbon atombearing the radical R^(3a) has S-configuration. The invention alsorelates to racemic mixtures of said R-enantiomer and said 5-enantiomeras well as to non-racemic mixtures, which are enriched with regard toeither said R-enantiomer or said S-enantiomer.

In particular groups of embodiments, the variable A in formula I is CH₂.

In further particular groups of embodiments, the variable A in formula Iis CH₂CH₂, CHFCH₂ or CF₂CH₂. If A is CHF₂CH, then the CH₂-group of A ispreferably attached to the nitrogen. If A is CF₂CH₂, then the CH₂-groupof A is preferably attached to the nitrogen. Especially, A is CH₂.

In particular groups of embodiments, the variable R⁴ in formula I isattached to the pyrimidine ring by a tertiary carbon atom such as intert.-butyl or 2-methyl-2-butyl. In particular, the variable R⁴ informula I is tert.-butyl.

A special group 1.1 of embodiments relates to compounds of the formulaI, where

-   -   A is CH₂, CH₂CH₂, CHFCH₂ or CF₂CH₂ and especially CH₂;    -   R¹ is 4-hydroxycyclohexyl, 3-hydroxycyclobutyl, or        3-(trifluoromethyl)-3-hydroxycyclobutyl;    -   R² is hydrogen;    -   R^(3a) and R^(3b) are hydrogen or either R^(3a) is methyl and        R^(3b) is hydrogen or R^(3a) is hydrogen and R^(3b) is methyl;        and    -   R⁴ is tert-butyl.

A further special group 1.2 of embodiments relates to compounds of theformula I, where

-   -   A is CH₂;    -   R¹ is trans 4-hydroxycyclohexyl or trans 3-hydroxycyclobutyl;    -   R² is hydrogen;    -   R^(3a) and R^(3b) are hydrogen or either R^(3a) is methyl and        R^(3b) is hydrogen or R^(3a) is hydrogen and R^(3b) is methyl;        and    -   R⁴ is tert-butyl.

In particular groups of embodiments, especially in the embodiments 1.1and 1.2, the variable R⁵ in formula I is preferably selected from thegroup consisting of C₁-C₆ alkyl, fluorinated C₁-C₃ alkyl, and C₃-C₅cycloalkyl, which is unsubstituted or carries 1 or 2 radicals selectedfrom fluorine, C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl. In these groupsof embodiments, R⁵ is in particular selected from the group consistingof difluoromethyl, trifluoromethyl, isopropyl, tert.-butyl, cyclopropyl,1-methylcyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl,2,2-difluorocyclopropyl, cyclobutyl, 1-fluorocyclobutyl,3,3-difluorocyclobutyl, and cyclopentyl and even more particularlyselected from the group consisting of cyclobutyl, difluoromethyl,trifluoromethyl, isopropyl and tert.-butyl and especially cyclobutyl.

In another particular groups of embodiments, the variable R⁵ in formulaI is selected from the group consisting of C₁-C₂-alkoxy-C₁-C₂-alkyl,fluorinated C₁-C₂-alkoxy-C₁-C₂-alkyl and hydroxy-C₁-C₄-alkyl, especiallyfrom the group consisting of C₁-C₂-alkoxy-C₁-C₂-alkyl andhydroxy-C₁-C₄-alkyl. In these groups of embodiments, R⁵ is in particularselected from the group consisting of methoxymethyl, ethoxymethyl,2-methoxyethyl, difluoromethoxymethyl, 2-(difluoromethoxy)ethyl,trifluoromethoxymethyl, 2-(trifluoromethoxy)ethyl,methoxydifluoromethyl, ethoxydifluoromethyl,2-methoxy-1,1-difluoroethyl, hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl and 2-hydroxy-2-methylpropyl, especially from the groupconsisting of methoxymethyl, ethoxymethyl, 2-methoxyethyl,2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methylpropyl.

In yet a further particular groups of embodiments, the variable R⁵ informula I is selected from the group consisting of oxetanyl, fluorinatedoxetanyl, oxolanyl, fluorinated oxolanyl, and C₃-C₅ cycloalkyl, whichcarries 1 or 2 radicals selected from hydroxyl, C₁-C₂-alkoxy andfluorinated C₁-C₂-alkoxy. In these groups of embodiments, R⁵ is inparticular selected from the group consisting of 2-oxetanyl, 3-oxetanyl,2-oxolanyl, 3-oxolanyl, 3-methoxycyclobutyl and 3-hydroxycyclobutyl.

A particular group (A) of embodiments of the invention relates tocompounds of the formula Ia

where R¹, R^(3a), R^(3b), R⁵ and A are as defined above, thephysiologically tolerated salts of these compounds and the N-oxidesthereof.

Another particular group (B) of embodiments of the invention relates tocompounds of the formula Ib

where R¹, R^(3a), R^(3b), R⁵ and A are as defined above, thephysiologically tolerated salts of these compounds and the N-oxidesthereof.

Another particular group (C) of embodiments of the invention relates tocompounds of the formula Ic

where R¹, R^(3a), R^(3b), R⁵ and A are as defined above, thephysiologically tolerated salts of these compounds and the N-oxidesthereof.

Special groups A-1.1, B-1.1 and C-1.1 of embodiments relates tocompounds of the formulae Ia, Ib and Ic, respectively, where

-   -   A is CH₂, CH₂CH₂, CHFCH₂ or CF₂CH₂, in particular CH₂;    -   R¹ is 4-hydroxycyclohexyl, 3-hydroxycyclobutyl, or        3-(trifluoromethyl)-3-hydroxycyclobutyl;    -   R² is hydrogen;    -   R^(3a) and R^(3b) are hydrogen or either R^(3a) is methyl and        R^(3b) is hydrogen or R^(3a) is hydrogen and R^(3b) is methyl;        and    -   R⁵ is as defined above.

Further special groups A-1.2, B-1.2 and C-1.2 of embodiments relates tocompounds of the formulae Ia, Ib and Ic, respectively, where

-   -   A is CH₂;    -   R¹ is trans 4-hydroxycyclohexyl or trans 3-hydroxycyclobutyl;    -   R² is hydrogen;    -   R^(3a) and R^(3b) are hydrogen or either R^(3a) is methyl and        R^(3b) is hydrogen or R^(3a) is hydrogen and R^(3b) is methyl;    -   R⁴ is tert-butyl; and    -   R⁵ is as defined above.

In particular groups of embodiments, especially in the embodiments ofgroups A-1.1, B-1.1, C-1.1, A-1.2, B-1.2 and C-1.2, the variable R⁵ informulae Ia, Ib and Ic is preferably selected from the group consistingof C₁-C₆ alkyl, fluorinated C₁-C₃ alkyl, and C₃-C₅ cycloalkyl, which isunsubstituted or carries 1 or 2 radicals selected from fluorine,C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl. In these groups of embodiments,R⁵ is in particular selected from the group consisting ofdifluoromethyl, trifluoromethyl, isopropyl, tert.-butyl, cyclopropyl,1-methylcyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl,2,2-difluorocyclopropyl, cyclobutyl, 1-fluorocyclobutyl,3,3-difluorocyclobutyl, and cyclopentyl and even more particularlyselected from the group consisting of cyclobutyl, difluoromethyl,trifluoromethyl, isopropyl and tert.-butyl and especially cyclobutyl.

In another particular groups of embodiments, especially in theembodiments of groups A-1.1, B-1.1, C-1.1, A-1.2, B-1.2 and C-1.2, thevariable R⁵ in formulae Ia, Ib and Ic is selected from the groupconsisting of C₁-C₂-alkoxy-C₁-C₂-alkyl, fluorinatedC₁-C₂-alkoxy-C₁-C₂-alkyl and hydroxy-C₁-C₄-alkyl, especially from thegroup consisting of C₁-C₂-alkoxy-C₁-C₂-alkyl and hydroxy-C₁-C₄-alkyl. Inthese groups of embodiments, R⁵ is in particular selected from the groupconsisting of methoxymethyl, ethoxymethyl, 2-methoxyethyl,difluoromethoxymethyl, 2-(difluoromethoxy)ethyl, trifluoromethoxymethyl,2-(trifluoromethoxy)ethyl, methoxydifluoromethyl, ethoxydifluoromethyl,2-methoxy-1,1-difluoroethyl, hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl and 2-hydroxy-2-methylpropyl, especially from the groupconsisting of methoxymethyl, ethoxymethyl, 2-methoxyethyl,2-hydroxyethyl, 2-hydroxypropyl and 2-hydroxy-2-methylpropyl.

In yet a further particular groups of embodiments, especially in theembodiments of groups A-1.1, B-1.1, C-1.1, A-1.2, B-1.2 and C-1.2, thevariable R⁵ in formulae Ia, Ib and Icisselected from the groupconsisting of oxetanyl, fluorinated oxetanyl, oxolanyl, fluorinatedoxolanyl, and C₃-C₅ cycloalkyl, which carries 1 or 2 radicals selectedfrom hydroxyl, C₁-C₂-alkoxy and fluorinated C₁-C₂-alkoxy. In thesegroups of embodiments, R⁵ is in particular selected from the groupconsisting of 2-oxetanyl, 3-oxetanyl, 2-oxolanyl, 3-oxolanyl,3-methoxycyclobutyl and 3-hydroxycyclobutyl.

More particularly, R⁵ in formula I and likewise in formulae Ia, Ib andIc and especially in the embodiments of groups A-1.1, B-1.1, C-1.1,A-1.2, B-1.2 and C-1.2, is cyclobutyl, difluoromethyl, trifluoromethyl,isopropyl and tert.-butyl. Especially, R⁵ in formula I and likewise informulae Ia, Ib and Ic especially in the embodiments of groups A-1.1,B-1.1, C-1.1, A-1.2, B-1.2 and C-1.2, is cyclobutyl.

In formula I and likewise in formulae Ia, Ib and Ic, the radicalR¹—C(═O)—NH and the radical R² be located either cis or trans withrespect to each other. The invention thus relates both to theessentially pure cis-isomer (cis/trans ratio is at least 9:1) and to theessentially pure trans-isomer (cis/trans ratio is at most 1:9) and. Theinvention also relates to mixtures of said cis-isomer and said transisomer where the cis/trans ratio is from 1:9 to 9:1.

In a particular group of embodiments, the radical R¹—C(═O)—NH and theradical R² predominately adopt cis-configuration. In this embodiment,the cis/trans-ratio is at least 8:1, in particular at least 9:1 andespecially at least 95:5.

In another particular group of embodiments, the radical R¹—C(═O)—NH andthe radical R² predominately adopt trans-configuration. In thisembodiment, the cis/trans-ratio is at most 1:8, in particular at most1:9 and especially at most 5:95.

Examples of compounds according to the present invention include but arenot limited to the compounds of the formulae Ia, Ib, and Ic summarizedin the following tables 1 to 36, where R¹, R^(3a), R^(3b) and R⁵ are asdefined in one row of table A. In table A, rows R^(3a) and R^(3b), theprefixes (S), (R) and (rac) indicate, whether the compound is theessentially pure R- or S-enantiomer or whether the compound is racemic.

Table 1: Compounds of the formula Ia, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 2: Compounds of the formula Ia, where A is CH₂CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 3: Compounds of the formula Ia, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 4: Compounds of the formula Ia, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 5: Compounds of the formula Ia, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on 1,4-cyclohexadiyl radical adopt cis-configuration.

Table 6: Compounds of the formula Ia, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents on the 1,4-cyclohexadiyl radical predominately adoptcis-configuration.

Table 7: Compounds of the formula Ia, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,4-cyclohexadiyl radical predominately adopt cis-configuration.

Table 8: Compounds of the formula Ia, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,4-cyclohexadiyl radical predominately adopt cis-configuration.

Table 9 Compounds of the formula Ia, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on the 1,4-cyclohexadiyl radical predominately adopttrans-configuration.

Table 10: Compounds of the formula Ia, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents on the 1,4-cyclohexadiyl radical predominately adopttrans-configuration.

Table 11: Compounds of the formula Ia, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,4-cyclohexadiyl radical predominately adopttrans-configuration.

Table 12: Compounds of the formula Ia, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,4-cyclohexadiyl radical predominately adopttrans-configuration.

Table 13: Compounds of the formula Ib, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 14: Compounds of the formula Ib, where A is CH₂CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 15: Compounds of the formula Ib, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 16: Compounds of the formula Ib, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 17: Compounds of the formula Ib, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on the 1,3-cyclopentadiyl radical predominately adoptcis-configuration.

Table 18: Compounds of the formula Ib, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents on the 1,3-cyclopentadiyl radical predominately adoptcis-configuration.

Table 19: Compounds of the formula Ib, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclopentadiyl radical predominately adopt cis-configuration.

Table 20: Compounds of the formula Ib, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclopentadiyl radical predominately adopt cis-configuration.

Table 21: Compounds of the formula Ib, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on the 1,3-cyclopentadiyl radical predominately adopttrans-configuration.

Table 22: Compounds of the formula Ib, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents 1,3-cyclopentadiyl radical predominately adopttrans-configuration.

Table 23: Compounds of the formula Ib, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclopentadiyl radical predominately adopttrans-configuration.

Table 24: Compounds of the formula Ib, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclopentadiyl radical predominately adopttrans-configuration.

Table 25: Compounds of the formula Ic, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 26: Compounds of the formula Ic, where A is CH₂CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A.

Table 27: Compounds of the formula Ic, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 28: Compounds of the formula Ic, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A.

Table 29: Compounds of the formula Ic, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on the 1,3-cyclobutadiyl radical predominately adoptcis-configuration.

Table 30: Compounds of the formula Ic, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents on the 1,3-cyclobutadiyl radical predominately adoptcis-configuration.

Table 31: Compounds of the formula Ic, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclobutadiyl radical predominately adopt cis-configuration.

Table 32: Compounds of the formula Ic, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclobutadiyl radical predominately adopt cis-configuration.

Table 33: Compounds of the formula Ic, where A is CH₂ and where R¹,R^(3a), R^(3b) and R⁵ are as defined in one row of table A and where thesubstituents on the 1,3-cyclobutadiyl radical predominately adopttrans-configuration.

Table 34: Compounds of the formula Ic, where A is A is CH₂CH₂ and whereR¹, R^(3a), R^(3b) and R⁵ are as defined in one row of table A and wherethe substituents 1,3-cyclobutadiyl radical predominately adopttrans-configuration.

Table 35: Compounds of the formula Ic, where A is CF₂CH₂, where the CH₂group of CF₂CH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclobutadiyl radical predominately adopttrans-configuration.

Table 36: Compounds of the formula Ic, where A is CHFCH₂, where the CH₂group of CHFCH₂ is attached to the nitrogen and where R¹, R^(3a), R^(3b)and R⁵ are as defined in one row of table A and where the substituentson the 1,3-cyclobutadiyl radical predominately adopttrans-configuration.

TABLE A # R¹ R^(3a) R^(3b) R⁵ 1. cis-4-hydroxycyclohexyl H H cyclobutyl2. cis-4-hydroxycyclohexyl H H 1-methylcyclopropyl 3.cis-4-hydroxycyclohexyl H H trifluoromethyl 4. cis-4-hydroxycyclohexyl HH difluoromethyl 5. cis-4-hydroxycyclohexyl H H 2-propyl 6.cis-4-hydroxycyclohexyl H H cyclopentyl 7. cis-4-hydroxycyclohexyl H H2-methyl-2-propyl 8. cis-4-hydroxycyclohexyl H H 2-methoxyethyl 9.cis-4-hydroxycyclohexyl H H methoxymethyl 10. trans-4-hydroxycyclohexylH H cyclobutyl 11. trans-4-hydroxycyclohexyl H H 1-methylcyclopropyl 12.trans-4-hydroxycyclohexyl H H trifluoromethyl 13.trans-4-hydroxycyclohexyl H H difluoromethyl 14.trans-4-hydroxycyclohexyl H H 2-propyl 15. trans-4-hydroxycyclohexyl H Hcyclopentyl 16. trans-4-hydroxycyclohexyl H H 2-methyl-2-propyl 17.trans-4-hydroxycyclohexyl H H 2-methoxyethyl 18.trans-4-hydroxycyclohexyl H H methoxymethyl 19. cis-4-hydroxycyclohexylH (rac) CH₃ cyclobutyl 20. cis-4-hydroxycyclohexyl H (rac) CH₃1-methylcyclopropyl 21. cis-4-hydroxycyclohexyl H (rac) CH₃trifluoromethyl 22. cis-4-hydroxycyclohexyl H (rac) CH₃ difluoromethyl23. cis-4-hydroxycyclohexyl H (rac) CH₃ 2-propyl 24.cis-4-hydroxycyclohexyl H (rac) CH₃ cyclopentyl 25.cis-4-hydroxycyclohexyl H (rac) CH₃ 2-methyl-2-propyl 26.cis-4-hydroxycyclohexyl H (rac) CH₃ 2-methoxyethyl 27.cis-4-hydroxycyclohexyl H (rac) CH₃ methoxymethyl 28.trans-4-hydroxycyclohexyl H (rac) CH₃ cyclobutyl 29.trans-4-hydroxycyclohexyl H (rac) CH₃ 1-methylcyclopropyl 30.trans-4-hydroxycyclohexyl H (rac) CH₃ trifluoromethyl 31.trans-4-hydroxycyclohexyl H (rac) CH₃ difluoromethyl 32.trans-4-hydroxycyclohexyl H (rac) CH₃ 2-propyl 33.trans-4-hydroxycyclohexyl H (rac) CH₃ cyclopentyl 34.trans-4-hydroxycyclohexyl H (rac) CH₃ 2-methyl-2-propyl 35.trans-4-hydroxycyclohexyl H (rac) CH₃ 2-methoxyethyl 36.trans-4-hydroxycyclohexyl H (rac) CH₃ methoxymethyl 37.cis-4-hydroxycyclohexyl H (S) CH₃ cyclobutyl 38. cis-4-hydroxycyclohexylH (S) CH₃ 1-methylcyclopropyl 39. cis-4-hydroxycyclohexyl H (S) CH₃trifluoromethyl 40. cis-4-hydroxycyclohexyl H (S) CH₃ difluoromethyl 41.cis-4-hydroxycyclohexyl H (S) CH₃ 2-propyl 42. cis-4-hydroxycyclohexyl H(S) CH₃ cyclopentyl 43. cis-4-hydroxycyclohexyl H (S) CH₃2-methyl-2-propyl 44. cis-4-hydroxycyclohexyl H (S) CH₃ 2-methoxyethyl45. cis-4-hydroxycyclohexyl H (S) CH₃ methoxymethyl 46.trans-4-hydroxycyclohexyl H (S) CH₃ cyclobutyl 47.trans-4-hydroxycyclohexyl H (S) CH₃ 1-methylcyclopropyl 48.trans-4-hydroxycyclohexyl H (S) CH₃ trifluoromethyl 49.trans-4-hydroxycyclohexyl H (S) CH₃ difluoromethyl 50.trans-4-hydroxycyclohexyl H (S) CH₃ 2-propyl 51.trans-4-hydroxycyclohexyl H (S) CH₃ cyclopentyl 52.trans-4-hydroxycyclohexyl H (S) CH₃ 2-methyl-2-propyl 53.trans-4-hydroxycyclohexyl H (S) CH₃ 2-methoxyethyl 54.trans-4-hydroxycyclohexyl H (S) CH₃ methoxymethyl 55.cis-4-hydroxycyclohexyl H (R) CH₃ cyclobutyl 56. cis-4-hydroxycyclohexylH (R) CH₃ 1-methylcyclopropyl 57. cis-4-hydroxycyclohexyl H (R) CH₃trifluoromethyl 58. cis-4-hydroxycyclohexyl H (R) CH₃ difluoromethyl 59.cis-4-hydroxycyclohexyl H (R) CH₃ 2-propyl 60. cis-4-hydroxycyclohexyl H(R) CH₃ cyclopentyl 61. cis-4-hydroxycyclohexyl H (R) CH₃2-methyl-2-propyl 62. cis-4-hydroxycyclohexyl H (R) CH₃ 2-methoxyethyl63. cis-4-hydroxycyclohexyl H (R) CH₃ methoxymethyl 64.trans-4-hydroxycyclohexyl H (R) CH₃ cyclobutyl 65.trans-4-hydroxycyclohexyl H (R) CH₃ 1-methylcyclopropyl 66.trans-4-hydroxycyclohexyl H (R) CH₃ trifluoromethyl 67.trans-4-hydroxycyclohexyl H (R) CH₃ difluoromethyl 68.trans-4-hydroxycyclohexyl H (R) CH₃ 2-propyl 69.trans-4-hydroxycyclohexyl H (R) CH₃ cyclopentyl 70.trans-4-hydroxycyclohexyl H (R) CH₃ 2-methyl-2-propyl 71.trans-4-hydroxycyclohexyl H (R) CH₃ 2-methoxyethyl 72.trans-4-hydroxycyclohexyl H (R) CH₃ methoxymethyl 73.trans-4-hydroxycyclohexyl (rac) CH₃ H cyclobutyl 74.cis-4-hydroxycyclohexyl (rac) CH₃ H 1-methylcyclopropyl 75.cis-4-hydroxycyclohexyl (rac) CH₃ H trifluoromethyl 76.cis-4-hydroxycyclohexyl (rac) CH₃ H difluoromethyl 77.cis-4-hydroxycyclohexyl (rac) CH₃ H 2-propyl 78. cis-4-hydroxycyclohexyl(rac) CH₃ H cyclopentyl 79. cis-4-hydroxycyclohexyl (rac) CH₃ H2-methyl-2-propyl 80. cis-4-hydroxycyclohexyl (rac) CH₃ H 2-methoxyethyl81. cis-4-hydroxycyclohexyl (rac) CH₃ H methoxymethyl 82.cis-4-hydroxycyclohexyl (rac) CH₃ H cyclobutyl 83.trans-4-hydroxycyclohexyl (rac) CH₃ H 1-methylcyclopropyl 84.trans-4-hydroxycyclohexyl (rac) CH₃ H trifluoromethyl 85.trans-4-hydroxycyclohexyl (rac) CH₃ H difluoromethyl 86.trans-4-hydroxycyclohexyl (rac) CH₃ H 2-propyl 87.trans-4-hydroxycyclohexyl (rac) CH₃ H cyclopentyl 88.trans-4-hydroxycyclohexyl (rac) CH₃ H 2-methyl-2-propyl 89.trans-4-hydroxycyclohexyl (rac) CH₃ H 2-methoxyethyl 90.trans-4-hydroxycyclohexyl (rac) CH₃ H methoxymethyl 91.cis-4-hydroxycyclohexyl (S) CH₃ H cyclobutyl 92. cis-4-hydroxycyclohexyl(S) CH₃ H 1-methylcyclopropyl 93. cis-4-hydroxycyclohexyl (S) CH₃ Htrifluoromethyl 94. cis-4-hydroxycyclohexyl (S) CH₃ H difluoromethyl 95.cis-4-hydroxycyclohexyl (S) CH₃ H 2-propyl 96. cis-4-hydroxycyclohexyl(S) CH₃ H cyclopentyl 97. cis-4-hydroxycyclohexyl (S) CH₃ H2-methyl-2-propyl 98. cis-4-hydroxycyclohexyl (S) CH₃ H 2-methoxyethyl99. cis-4-hydroxycyclohexyl (S) CH₃ H methoxymethyl 100.trans-4-hydroxycyclohexyl (S) CH₃ H cyclobutyl 101.trans-4-hydroxycyclohexyl (S) CH₃ H 1-methylcyclopropyl 102.trans-4-hydroxycyclohexyl (S) CH₃ H trifluoromethyl 103.trans-4-hydroxycyclohexyl (S) CH₃ H difluoromethyl 104.trans-4-hydroxycyclohexyl (S) CH₃ H 2-propyl 105.trans-4-hydroxycyclohexyl (S) CH₃ H cyclopentyl 106.trans-4-hydroxycyclohexyl (S) CH₃ H 2-methyl-2-propyl 107.trans-4-hydroxycyclohexyl (S) CH₃ H 2-methoxyethyl 108.trans-4-hydroxycyclohexyl (S) CH₃ H methoxymethyl 109.cis-4-hydroxycyclohexyl (R) CH₃ H cyclobutyl 110.cis-4-hydroxycyclohexyl (R) CH₃ H 1-methylcyclopropyl 111.cis-4-hydroxycyclohexyl (R) CH₃ H trifluoromethyl 112.cis-4-hydroxycyclohexyl (R) CH₃ H difluoromethyl 113.cis-4-hydroxycyclohexyl (R) CH₃ H 2-propyl 114. cis-4-hydroxycyclohexyl(R) CH₃ H cyclopentyl 115. cis-4-hydroxycyclohexyl (R) CH₃ H2-methyl-2-propyl 116. cis-4-hydroxycyclohexyl (R) CH₃ H 2-methoxyethyl117. cis-4-hydroxycyclohexyl (R) CH₃ H methoxymethyl 118.trans-4-hydroxycyclohexyl (R) CH₃ H cyclobutyl 119.trans-4-hydroxycyclohexyl (R) CH₃ H 1-methylcyclopropyl 120.trans-4-hydroxycyclohexyl (R) CH₃ H trifluoromethyl 121.trans-4-hydroxycyclohexyl (R) CH₃ H difluoromethyl 122.trans-4-hydroxycyclohexyl (R) CH₃ H 2-propyl 123.trans-4-hydroxycyclohexyl (R) CH₃ H cyclopentyl 124.trans-4-hydroxycyclohexyl (R) CH₃ H 2-methyl-2-propyl 125.trans-4-hydroxycyclohexyl (R) CH₃ H 2-methoxyethyl 126.trans-4-hydroxycyclohexyl (R) CH₃ H methoxymethyl 127.cis-3-hydroxycyclobutyl H H cyclobutyl 128. cis-3-hydroxycyclobutyl H H1-methylcyclopropyl 129. cis-3-hydroxycyclobutyl H H trifluoromethyl130. cis-3-hydroxycyclobutyl H H difluoromethyl 131.cis-3-hydroxycyclobutyl H H 2-propyl 132. cis-3-hydroxycyclobutyl H Hcyclopentyl 133. cis-3-hydroxycyclobutyl H H 2-methyl-2-propyl 134.cis-3-hydroxycyclobutyl H H 2-methoxyethyl 135. cis-3-hydroxycyclobutylH H methoxymethyl 136. trans-3-hydroxycyclobutyl H H cyclobutyl 137.trans-3-hydroxycyclobutyl H H 1-methylcyclopropyl 138.trans-3-hydroxycyclobutyl H H trifluoromethyl 139.trans-3-hydroxycyclobutyl H H difluoromethyl 140.trans-3-hydroxycyclobutyl H H 2-propyl 141. trans-3-hydroxycyclobutyl HH cyclopentyl 142. trans-3-hydroxycyclobutyl H H 2-methyl-2-propyl 143.trans-3-hydroxycyclobutyl H H 2-methoxyethyl 144.trans-3-hydroxycyclobutyl H H methoxymethyl 145. cis-3-hydroxycyclobutylH (rac) CH₃ cyclobutyl 146. cis-3-hydroxycyclobutyl H (rac) CH₃1-methylcyclopropyl 147. cis-3-hydroxycyclobutyl H (rac) CH₃trifluoromethyl 148. cis-3-hydroxycyclobutyl H (rac) CH₃ difluoromethyl149. cis-3-hydroxycyclobutyl H (rac) CH₃ 2-propyl 150.cis-3-hydroxycyclobutyl H (rac) CH₃ cyclopentyl 151.cis-3-hydroxycyclobutyl H (rac) CH₃ 2-methyl-2-propyl 152.cis-3-hydroxycyclobutyl H (rac) CH₃ 2-methoxyethyl 153.cis-3-hydroxycyclobutyl H (rac) CH₃ methoxymethyl 154.trans-3-hydroxycyclobutyl H (rac) CH₃ cyclobutyl 155.trans-3-hydroxycyclobutyl H (rac) CH₃ 1-methylcyclopropyl 156.trans-3-hydroxycyclobutyl H (rac) CH₃ trifluoromethyl 157.trans-3-hydroxycyclobutyl H (rac) CH₃ difluoromethyl 158.trans-3-hydroxycyclobutyl H (rac) CH₃ 2-propyl 159.trans-3-hydroxycyclobutyl H (rac) CH₃ cyclopentyl 160.trans-3-hydroxycyclobutyl H (rac) CH₃ 2-methyl-2-propyl 161.trans-3-hydroxycyclobutyl H (rac) CH₃ 2-methoxyethyl 162.trans-3-hydroxycyclobutyl H (rac) CH₃ methoxymethyl 163.cis-3-hydroxycyclobutyl H (S) CH₃ cyclobutyl 164.cis-3-hydroxycyclobutyl H (S) CH₃ 1-methylcyclopropyl 165.cis-3-hydroxycyclobutyl H (S) CH₃ trifluoromethyl 166.cis-3-hydroxycyclobutyl H (S) CH₃ difluoromethyl 167.cis-3-hydroxycyclobutyl H (S) CH₃ 2-propyl 168. cis-3-hydroxycyclobutylH (S) CH₃ cyclopentyl 169. cis-3-hydroxycyclobutyl H (S) CH₃2-methyl-2-propyl 170. cis-3-hydroxycyclobutyl H (S) CH₃ 2-methoxyethyl171. cis-3-hydroxycyclobutyl H (S) CH₃ methoxymethyl 172.trans-3-hydroxycyclobutyl H (S) CH₃ cyclobutyl 173.trans-3-hydroxycyclobutyl H (S) CH₃ 1-methylcyclopropyl 174.trans-3-hydroxycyclobutyl H (S) CH₃ trifluoromethyl 175.trans-3-hydroxycyclobutyl H (S) CH₃ difluoromethyl 176.trans-3-hydroxycyclobutyl H (S) CH₃ 2-propyl 177.trans-3-hydroxycyclobutyl H (S) CH₃ cyclopentyl 178.trans-3-hydroxycyclobutyl H (S) CH₃ 2-methyl-2-propyl 179.trans-3-hydroxycyclobutyl H (S) CH₃ 2-methoxyethyl 180.trans-3-hydroxycyclobutyl H (S) CH₃ methoxymethyl 181.cis-3-hydroxycyclobutyl H (R) CH₃ cyclobutyl 182.cis-3-hydroxycyclobutyl H (R) CH₃ 1-methylcyclopropyl 183.cis-3-hydroxycyclobutyl H (R) CH₃ trifluoromethyl 184.cis-3-hydroxycyclobutyl H (R) CH₃ difluoromethyl 185.cis-3-hydroxycyclobutyl H (R) CH₃ 2-propyl 186. cis-3-hydroxycyclobutylH (R) CH₃ cyclopentyl 187. cis-3-hydroxycyclobutyl H (R) CH₃2-methyl-2-propyl 188. cis-3-hydroxycyclobutyl H (R) CH₃ 2-methoxyethyl189. cis-3-hydroxycyclobutyl H (R) CH₃ methoxymethyl 190.trans-3-hydroxycyclobutyl H (R) CH₃ cyclobutyl 191.trans-3-hydroxycyclobutyl H (R) CH₃ 1-methylcyclopropyl 192.trans-3-hydroxycyclobutyl H (R) CH₃ trifluoromethyl 193.trans-3-hydroxycyclobutyl H (R) CH₃ difluoromethyl 194.trans-3-hydroxycyclobutyl H (R) CH₃ 2-propyl 195.trans-3-hydroxycyclobutyl H (R) CH₃ cyclopentyl 196.trans-3-hydroxycyclobutyl H (R) CH₃ 2-methyl-2-propyl 197.trans-3-hydroxycyclobutyl H (R) CH₃ 2-methoxyethyl 198.trans-3-hydroxycyclobutyl H (R) CH₃ methoxymethyl 199.cis-3-hydroxycyclobutyl (rac) CH₃ H cyclobutyl 200.cis-3-hydroxycyclobutyl (rac) CH₃ H 1-methylcyclopropyl 201.cis-3-hydroxycyclobutyl (rac) CH₃ H trifluoromethyl 202.cis-3-hydroxycyclobutyl (rac) CH₃ H difluoromethyl 203.cis-3-hydroxycyclobutyl (rac) CH₃ H 2-propyl 204.cis-3-hydroxycyclobutyl (rac) CH₃ H cyclopentyl 205.cis-3-hydroxycyclobutyl (rac) CH₃ H 2-methyl-2-propyl 206.cis-3-hydroxycyclobutyl (rac) CH₃ H 2-methoxyethyl 207.cis-3-hydroxycyclobutyl (rac) CH₃ H methoxymethyl 208.trans-3-hydroxycyclobutyl (rac) CH₃ H cyclobutyl 209.trans-3-hydroxycyclobutyl (rac) CH₃ H 1-methylcyclopropyl 210.trans-3-hydroxycyclobutyl (rac) CH₃ H trifluoromethyl 211.trans-3-hydroxycyclobutyl (rac) CH₃ H difluoromethyl 212.trans-3-hydroxycyclobutyl (rac) CH₃ H 2-propyl 213.trans-3-hydroxycyclobutyl (rac) CH₃ H cyclopentyl 214.trans-3-hydroxycyclobutyl (rac) CH₃ H 2-methyl-2-propyl 215.trans-3-hydroxycyclobutyl (rac) CH₃ H 2-methoxyethyl 216.trans-3-hydroxycyclobutyl (rac) CH₃ H methoxymethyl 217.cis-3-hydroxycyclobutyl (S) CH₃ H cyclobutyl 218.cis-3-hydroxycyclobutyl (S) CH₃ H 1-methylcyclopropyl 219.cis-3-hydroxycyclobutyl (S) CH₃ H trifluoromethyl 220.cis-3-hydroxycyclobutyl (S) CH₃ H difluoromethyl 221.cis-3-hydroxycyclobutyl (S) CH₃ H 2-propyl 222. cis-3-hydroxycyclobutyl(S) CH₃ H cyclopentyl 223. cis-3-hydroxycyclobutyl (S) CH₃ H2-methyl-2-propyl 224. cis-3-hydroxycyclobutyl (S) CH₃ H 2-methoxyethyl225. cis-3-hydroxycyclobutyl (S) CH₃ H methoxymethyl 226.trans-3-hydroxycyclobutyl (S) CH₃ H cyclobutyl 227.trans-3-hydroxycyclobutyl (S) CH₃ H 1-methylcyclopropyl 228.trans-3-hydroxycyclobutyl (S) CH₃ H trifluoromethyl 229.trans-3-hydroxycyclobutyl (S) CH₃ H difluoromethyl 230.trans-3-hydroxycyclobutyl (S) CH₃ H 2-propyl 231.trans-3-hydroxycyclobutyl (S) CH₃ H cyclopentyl 232.trans-3-hydroxycyclobutyl (S) CH₃ H 2-methyl-2-propyl 233.trans-3-hydroxycyclobutyl (S) CH₃ H 2-methoxyethyl 234.trans-3-hydroxycyclobutyl (S) CH₃ H methoxymethyl 235.cis-3-hydroxycyclobutyl (R) CH₃ H cyclobutyl 236.cis-3-hydroxycyclobutyl (R) CH₃ H 1-methylcyclopropyl 237.cis-3-hydroxycyclobutyl (R) CH₃ H trifluoromethyl 238.cis-3-hydroxycyclobutyl (R) CH₃ H difluoromethyl 239.cis-3-hydroxycyclobutyl (R) CH₃ H 2-propyl 240. cis-3-hydroxycyclobutyl(R) CH₃ H cyclopentyl 241. cis-3-hydroxycyclobutyl (R) CH₃ H2-methyl-2-propyl 242. cis-3-hydroxycyclobutyl (R) CH₃ H 2-methoxyethyl243. cis-3-hydroxycyclobutyl (R) CH₃ H methoxymethyl 244.trans-3-hydroxycyclobutyl (R) CH₃ H cyclobutyl 245.trans-3-hydroxycyclobutyl (R) CH₃ H 1-methylcyclopropyl 246.trans-3-hydroxycyclobutyl (R) CH₃ H trifluoromethyl 247.trans-3-hydroxycyclobutyl (R) CH₃ H difluoromethyl 248.trans-3-hydroxycyclobutyl (R) CH₃ H 2-propyl 249.trans-3-hydroxycyclobutyl (R) CH₃ H cyclopentyl 250.trans-3-hydroxycyclobutyl (R) CH₃ H 2-methyl-2-propyl 251.trans-3-hydroxycyclobutyl (R) CH₃ H 2-methoxyethyl 252.trans-3-hydroxycyclobutyl (R) CH₃ H methoxymethyl 253.3-hydroxy-3-trifluoro- H H cyclobutyl methylcyclobutyl 254.3-hydroxy-3-trifluoro- H H 1-methylcyclopropyl methylcyclobutyl 255.3-hydroxy-3-trifluoro- H H trifluoromethyl methylcyclobutyl 256.3-hydroxy-3-trifluoro- H H difluoromethyl methylcyclobutyl 257.3-hydroxy-3-trifluoro- H H 2-propyl methylcyclobutyl 258.3-hydroxy-3-trifluoro- H H cyclopentyl methylcyclobutyl 259.3-hydroxy-3-trifluoro- H H 2-methyl-2-propyl methylcyclobutyl 260.3-hydroxy-3-trifluoro- H H 2-methoxyethyl methylcyclobutyl 261.3-hydroxy-3-trifluoro- H H methoxymethyl methylcyclobutyl 262.3-hydroxy-3-trifluoro- H (rac) CH₃ cyclobutyl methylcyclobutyl 263.3-hydroxy-3-trifluoro- H (rac) CH₃ 1-methylcyclopropyl methylcyclobutyl264. 3-hydroxy-3-trifluoro- H (rac) CH₃ trifluoromethyl methylcyclobutyl265. 3-hydroxy-3-trifluoro- H (rac) CH₃ difluoromethyl methylcyclobutyl266. 3-hydroxy-3-trifluoro- H (rac) CH₃ 2-propyl methylcyclobutyl 267.3-hydroxy-3-trifluoro- H (rac) CH₃ cyclopentyl methylcyclobutyl 268.3-hydroxy-3-trifluoro- H (rac) CH₃ 2-methyl-2-propyl methylcyclobutyl269. 3-hydroxy-3-trifluoro- H (rac) CH₃ 2-methoxyethyl methylcyclobutyl270. 3-hydroxy-3-trifluoro- H (rac) CH₃ methoxymethyl methylcyclobutyl271. 3-hydroxy-3-trifluoro- H (S) CH₃ cyclobutyl methylcyclobutyl 272.3-hydroxy-3-trifluoro- H (S) CH₃ 1-methylcyclopropyl methylcyclobutyl273. 3-hydroxy-3-trifluoro- H (S) CH₃ trifluoromethyl methylcyclobutyl274. 3-hydroxy-3-trifluoro- H (S) CH₃ difluoromethyl methylcyclobutyl275. 3-hydroxy-3-trifluoro- H (S) CH₃ 2-propyl methylcyclobutyl 276.3-hydroxy-3-trifluoro- H (S) CH₃ cyclopentyl methylcyclobutyl 277.3-hydroxy-3-trifluoro- H (S) CH₃ 2-methyl-2-propyl methylcyclobutyl 278.3-hydroxy-3-trifluoro- H (S) CH₃ 2-methoxyethyl methylcyclobutyl 279.3-hydroxy-3-trifluoro- H (S) CH₃ methoxymethyl methylcyclobutyl 280.3-hydroxy-3-trifluoro- H (R) CH₃ cyclobutyl methylcyclobutyl 281.3-hydroxy-3-trifluoro- H (R) CH₃ 1-methylcyclopropyl methylcyclobutyl282. 3-hydroxy-3-trifluoro- H (R) CH₃ trifluoromethyl methylcyclobutyl283. 3-hydroxy-3-trifluoro- H (R) CH₃ difluoromethyl methylcyclobutyl284. 3-hydroxy-3-trifluoro- H (R) CH₃ 2-propyl methylcyclobutyl 285.3-hydroxy-3-trifluoro- H (R) CH₃ cyclopentyl methylcyclobutyl 286.3-hydroxy-3-trifluoro- H (R) CH₃ 2-methyl-2-propyl methylcyclobutyl 287.3-hydroxy-3-trifluoro- H (R) CH₃ 2-methoxyethyl methylcyclobutyl 288.3-hydroxy-3-trifluoro- H (R) CH₃ methoxymethyl methylcyclobutyl 289.3-hydroxy-3-trifluoro- (rac) CH₃ H cyclobutyl methylcyclobutyl 290.3-hydroxy-3-trifluoro- (rac) CH₃ H 1-methylcyclopropyl methylcyclobutyl291. 3-hydroxy-3-trifluoro- (rac) CH₃ H trifluoromethyl methylcyclobutyl292. 3-hydroxy-3-trifluoro- (rac) CH₃ H difluoromethyl methylcyclobutyl293. 3-hydroxy-3-trifluoro- (rac) CH₃ H 2-propyl methylcyclobutyl 294.3-hydroxy-3-trifluoro- (rac) CH₃ H cyclopentyl methylcyclobutyl 295.3-hydroxy-3-trifluoro- (rac) CH₃ H 2-methyl-2-propyl methylcyclobutyl296. 3-hydroxy-3-trifluoro- (rac) CH₃ H 2-methoxyethyl methylcyclobutyl297. 3-hydroxy-3-trifluoro- (rac) CH₃ H methoxymethyl methylcyclobutyl298. 3-hydroxy-3-trifluoro- (S) CH₃ H cyclobutyl methylcyclobutyl 299.3-hydroxy-3-trifluoro- (S) CH₃ H 1-methylcyclopropyl methylcyclobutyl300. 3-hydroxy-3-trifluoro- (S) CH₃ H trifluoromethyl methylcyclobutyl301. 3-hydroxy-3-trifluoro- (S) CH₃ H difluoromethyl methylcyclobutyl302. 3-hydroxy-3-trifluoro- (S) CH₃ H 2-propyl methylcyclobutyl 303.3-hydroxy-3-trifluoro- (S) CH₃ H cyclopentyl methylcyclobutyl 304.3-hydroxy-3-trifluoro- (S) CH₃ H 2-methyl-2-propyl methylcyclobutyl 305.3-hydroxy-3-trifluoro- (S) CH₃ H 2-methoxyethyl methylcyclobutyl 306.3-hydroxy-3-trifluoro- (S) CH₃ H methoxymethyl methylcyclobutyl 307.3-hydroxy-3-trifluoro- (R) CH₃ H cyclobutyl methylcyclobutyl 308.3-hydroxy-3-trifluoro- (R) CH₃ H 1-methylcyclopropyl methylcyclobutyl309. 3-hydroxy-3-trifluoro- (R) CH₃ H trifluoromethyl methylcyclobutyl310. 3-hydroxy-3-trifluoro- (R) CH₃ H difluoromethyl methylcyclobutyl311. 3-hydroxy-3-trifluoro- (R) CH₃ H 2-propyl methylcyclobutyl 312.3-hydroxy-3-trifluoro- (R) CH₃ H cyclopentyl methylcyclobutyl 313.3-hydroxy-3-trifluoro- (R) CH₃ H 2-methyl-2-propyl methylcyclobutyl 314.3-hydroxy-3-trifluoro- (R) CH₃ H 2-methoxyethyl methylcyclobutyl 315.3-hydroxy-3-trifluoro- (R) CH₃ H methoxymethyl methylcyclobutyl 316.cis-4-methoxycyclohexyl H H cyclobutyl 317. cis-4-methoxycyclohexyl H H1-methylcyclopropyl 318. cis-4-methoxycyclohexyl H H trifluoromethyl319. cis-4-methoxycyclohexyl H H difluoromethyl 320.cis-4-methoxycyclohexyl H H 2-propyl 321. cis-4-methoxycyclohexyl H Hcyclopentyl 322. cis-4-methoxycyclohexyl H H 2-methyl-2-propyl 323.cis-4-methoxycyclohexyl H H 2-methoxyethyl 324. cis-4-methoxycyclohexylH H methoxymethyl 325. trans-4-methoxycyclohexyl H H cyclobutyl 326.trans-4-methoxycyclohexyl H H 1-methylcyclopropyl 327.trans-4-methoxycyclohexyl H H trifluoromethyl 328.trans-4-methoxycyclohexyl H H difluoromethyl 329.trans-4-methoxycyclohexyl H H 2-propyl 330. trans-4-methoxycyclohexyl HH cyclopentyl 331. trans-4-methoxycyclohexyl H H 2-methyl-2-propyl 332.trans-4-methoxycyclohexyl H H 2-methoxyethyl 333.trans-4-methoxycyclohexyl H H methoxymethyl 334. cis-4-methoxycyclohexylH (rac) CH₃ cyclobutyl 335. cis-4-methoxycyclohexyl H (rac) CH₃1-methylcyclopropyl 336. cis-4-methoxycyclohexyl H (rac) CH₃trifluoromethyl 337. cis-4-methoxycyclohexyl H (rac) CH₃ difluoromethyl338. cis-4-methoxycyclohexyl H (rac) CH₃ 2-propyl 339.cis-4-methoxycyclohexyl H (rac) CH₃ cyclopentyl 340.cis-4-methoxycyclohexyl H (rac) CH₃ 2-methyl-2-propyl 341.cis-4-methoxycyclohexyl H (rac) CH₃ 2-methoxyethyl 342.cis-4-methoxycyclohexyl H (rac) CH₃ methoxymethyl 343.trans-4-methoxycyclohexyl H (rac) CH₃ cyclobutyl 344.trans-4-methoxycyclohexyl H (rac) CH₃ 1-methylcyclopropyl 345.trans-4-methoxycyclohexyl H (rac) CH₃ trifluoromethyl 346.trans-4-methoxycyclohexyl H (rac) CH₃ difluoromethyl 347.trans-4-methoxycyclohexyl H (rac) CH₃ 2-propyl 348.trans-4-methoxycyclohexyl H (rac) CH₃ cyclopentyl 349.trans-4-methoxycyclohexyl H (rac) CH₃ 2-methyl-2-propyl 350.trans-4-methoxycyclohexyl H (rac) CH₃ 2-methoxyethyl 351.trans-4-methoxycyclohexyl H (rac) CH₃ methoxymethyl 352.cis-4-methoxycyclohexyl H (S) CH₃ cyclobutyl 353.cis-4-methoxycyclohexyl H (S) CH₃ 1-methylcyclopropyl 354.cis-4-methoxycyclohexyl H (S) CH₃ trifluoromethyl 355.cis-4-methoxycyclohexyl H (S) CH₃ difluoromethyl 356.cis-4-methoxycyclohexyl H (S) CH₃ 2-propyl 357. cis-4-methoxycyclohexylH (S) CH₃ cyclopentyl 358. cis-4-methoxycyclohexyl H (S) CH₃2-methyl-2-propyl 359. cis-4-methoxycyclohexyl H (S) CH₃ 2-methoxyethyl360. cis-4-methoxycyclohexyl H (S) CH₃ methoxymethyl 361.trans-4-methoxycyclohexyl H (S) CH₃ cyclobutyl 362.trans-4-methoxycyclohexyl H (S) CH₃ 1-methylcyclopropyl 363.trans-4-methoxycyclohexyl H (S) CH₃ trifluoromethyl 364.trans-4-methoxycyclohexyl H (S) CH₃ difluoromethyl 365.trans-4-methoxycyclohexyl H (S) CH₃ 2-propyl 366.trans-4-methoxycyclohexyl H (S) CH₃ cyclopentyl 367.trans-4-methoxycyclohexyl H (S) CH₃ 2-methyl-2-propyl 368.trans-4-methoxycyclohexyl H (S) CH₃ 2-methoxyethyl 369.trans-4-methoxycyclohexyl H (S) CH₃ methoxymethyl 370.cis-4-methoxycyclohexyl H (R) CH₃ cyclobutyl 371.cis-4-methoxycyclohexyl H (R) CH₃ 1-methylcyclopropyl 372.cis-4-methoxycyclohexyl H (R) CH₃ trifluoromethyl 373.cis-4-methoxycyclohexyl H (R) CH₃ difluoromethyl 374.cis-4-methoxycyclohexyl H (R) CH₃ 2-propyl 375. cis-4-methoxycyclohexylH (R) CH₃ cyclopentyl 376. cis-4-methoxycyclohexyl H (R) CH₃2-methyl-2-propyl 377. cis-4-methoxycyclohexyl H (R) CH₃ 2-methoxyethyl378. cis-4-methoxycyclohexyl H (R) CH₃ methoxymethyl 379.trans-4-methoxycyclohexyl H (R) CH₃ cyclobutyl 380.trans-4-methoxycyclohexyl H (R) CH₃ 1-methylcyclopropyl 381.trans-4-methoxycyclohexyl H (R) CH₃ trifluoromethyl 382.trans-4-methoxycyclohexyl H (R) CH₃ difluoromethyl 383.trans-4-methoxycyclohexyl H (R) CH₃ 2-propyl 384.trans-4-methoxycyclohexyl H (R) CH₃ cyclopentyl 385.trans-4-methoxycyclohexyl H (R) CH₃ 2-methyl-2-propyl 386.trans-4-methoxycyclohexyl H (R) CH₃ 2-methoxyethyl 387.trans-4-methoxycyclohexyl H (R) CH₃ methoxymethyl 388.cis-4-methoxycyclohexyl (rac) CH₃ H cyclobutyl 389.cis-4-methoxycyclohexyl (rac) CH₃ H 1-methylcyclopropyl 390.cis-4-methoxycyclohexyl (rac) CH₃ H trifluoromethyl 391.cis-4-methoxycyclohexyl (rac) CH₃ H difluoromethyl 392.cis-4-methoxycyclohexyl (rac) CH₃ H 2-propyl 393.cis-4-methoxycyclohexyl (rac) CH₃ H cyclopentyl 394.cis-4-methoxycyclohexyl (rac) CH₃ H 2-methyl-2-propyl 395.cis-4-methoxycyclohexyl (rac) CH₃ H 2-methoxyethyl 396.cis-4-methoxycyclohexyl (rac) CH₃ H methoxymethyl 397.trans-4-methoxycyclohexyl (rac) CH₃ H cyclobutyl 398.trans-4-methoxycyclohexyl (rac) CH₃ H 1-methylcyclopropyl 399.trans-4-methoxycyclohexyl (rac) CH₃ H trifluoromethyl 400.trans-4-methoxycyclohexyl (rac) CH₃ H difluoromethyl 401.trans-4-methoxycyclohexyl (rac) CH₃ H 2-propyl 402.trans-4-methoxycyclohexyl (rac) CH₃ H cyclopentyl 403.trans-4-methoxycyclohexyl (rac) CH₃ H 2-methyl-2-propyl 404.trans-4-methoxycyclohexyl (rac) CH₃ H 2-methoxyethyl 405.trans-4-methoxycyclohexyl (rac) CH₃ H methoxymethyl 406.cis-4-methoxycyclohexyl (S) CH₃ H cyclobutyl 407.cis-4-methoxycyclohexyl (S) CH₃ H 1-methylcyclopropyl 408.cis-4-methoxycyclohexyl (S) CH₃ H trifluoromethyl 409.cis-4-methoxycyclohexyl (S) CH₃ H difluoromethyl 410.cis-4-methoxycyclohexyl (S) CH₃ H 2-propyl 411. cis-4-methoxycyclohexyl(S) CH₃ H cyclopentyl 412. cis-4-methoxycyclohexyl (S) CH₃ H2-methyl-2-propyl 413. cis-4-methoxycyclohexyl (S) CH₃ H 2-methoxyethyl414. cis-4-methoxycyclohexyl (S) CH₃ H methoxymethyl 415.trans-4-methoxycyclohexyl (S) CH₃ H cyclobutyl 416.trans-4-methoxycyclohexyl (S) CH₃ H 1-methylcyclopropyl 417.trans-4-methoxycyclohexyl (S) CH₃ H trifluoromethyl 418.trans-4-methoxycyclohexyl (S) CH₃ H difluoromethyl 419.trans-4-methoxycyclohexyl (S) CH₃ H 2-propyl 420.trans-4-methoxycyclohexyl (S) CH₃ H cyclopentyl 421.trans-4-methoxycyclohexyl (S) CH₃ H 2-methyl-2-propyl 422.trans-4-methoxycyclohexyl (S) CH₃ H 2-methoxyethyl 423.trans-4-methoxycyclohexyl (S) CH₃ H methoxymethyl 424.cis-4-methoxycyclohexyl (R) CH₃ H cyclobutyl 425.cis-4-methoxycyclohexyl (R) CH₃ H 1-methylcyclopropyl 426.cis-4-methoxycyclohexyl (R) CH₃ H trifluoromethyl 427.cis-4-methoxycyclohexyl (R) CH₃ H difluoromethyl 428.cis-4-methoxycyclohexyl (R) CH₃ H 2-propyl 429. cis-4-methoxycyclohexyl(R) CH₃ H cyclopentyl 430. cis-4-methoxycyclohexyl (R) CH₃ H2-methyl-2-propyl 431. cis-4-methoxycyclohexyl (R) CH₃ H 2-methoxyethyl432. cis-4-methoxycyclohexyl (R) CH₃ H methoxymethyl 433.trans-4-methoxycyclohexyl (R) CH₃ H cyclobutyl 434.trans-4-methoxycyclohexyl (R) CH₃ H 1-methylcyclopropyl 435.trans-4-methoxycyclohexyl (R) CH₃ H trifluoromethyl 436.trans-4-methoxycyclohexyl (R) CH₃ H difluoromethyl 437.trans-4-methoxycyclohexyl (R) CH₃ H 2-propyl 438.trans-4-methoxycyclohexyl (R) CH₃ H cyclopentyl 439.trans-4-methoxycyclohexyl (R) CH₃ H 2-methyl-2-propyl 440.trans-4-methoxycyclohexyl (R) CH₃ H 2-methoxyethyl 441.trans-4-methoxycyclohexyl (R) CH₃ H methoxymethyl 442. 4-oxocyclohexyl HH cyclobutyl 443. 4-oxocyclohexyl H H 1-methylcyclopropyl 444.4-oxocyclohexyl H H trifluoromethyl 445. 4-oxocyclohexyl H Hdifluoromethyl 446. 4-oxocyclohexyl H H 2-propyl 447. 4-oxocyclohexyl HH cyclopentyl 448. 4-oxocyclohexyl H H 2-methyl-2-propyl 449.4-oxocyclohexyl H H 2-methoxyethyl 450. 4-oxocyclohexyl H Hmethoxymethyl 451. 4-oxocyclohexyl H (rac) CH₃ cyclobutyl 452.4-oxocyclohexyl H (rac) CH₃ 1-methylcyclopropyl 453. 4-oxocyclohexyl H(rac) CH₃ trifluoromethyl 454. 4-oxocyclohexyl H (rac) CH₃difluoromethyl 455. 4-oxocyclohexyl H (rac) CH₃ 2-propyl 456.4-oxocyclohexyl H (rac) CH₃ cyclopentyl 457. 4-oxocyclohexyl H (rac) CH₃2-methyl-2-propyl 458. 4-oxocyclohexyl H (rac) CH₃ 2-methoxyethyl 459.4-oxocyclohexyl H (rac) CH₃ methoxymethyl 460. 4-oxocyclohexyl H (S) CH₃cyclobutyl 461. 4-oxocyclohexyl H (S) CH₃ 1-methylcyclopropyl 462.4-oxocyclohexyl H (S) CH₃ trifluoromethyl 463. 4-oxocyclohexyl H (S) CH₃difluoromethyl 464. 4-oxocyclohexyl H (S) CH₃ 2-propyl 465.4-oxocyclohexyl H (S) CH₃ cyclopentyl 466. 4-oxocyclohexyl H (S) CH₃2-methyl-2-propyl 467. 4-oxocyclohexyl H (S) CH₃ 2-methoxyethyl 468.4-oxocyclohexyl H (S) CH₃ methoxymethyl 469. 4-oxocyclohexyl H (R) CH₃cyclobutyl 470. 4-oxocyclohexyl H (R) CH₃ 1-methylcyclopropyl 471.4-oxocyclohexyl H (R) CH₃ trifluoromethyl 472. 4-oxocyclohexyl H (R) CH₃difluoromethyl 473. 4-oxocyclohexyl H (R) CH₃ 2-propyl 474.4-oxocyclohexyl H (R) CH₃ cyclopentyl 475. 4-oxocyclohexyl H (R) CH₃2-methyl-2-propyl 476. 4-oxocyclohexyl H (R) CH₃ 2-methoxyethyl 477.4-oxocyclohexyl H (R) CH₃ methoxymethyl 478. 4-oxocyclohexyl (rac) CH₃ Hcyclobutyl 479. 4-oxocyclohexyl (rac) CH₃ H 1-methylcyclopropyl 480.4-oxocyclohexyl (rac) CH₃ H trifluoromethyl 481. 4-oxocyclohexyl (rac)CH₃ H difluoromethyl 482. 4-oxocyclohexyl (rac) CH₃ H 2-propyl 483.4-oxocyclohexyl (rac) CH₃ H cyclopentyl 484. 4-oxocyclohexyl (rac) CH₃ H2-methyl-2-propyl 485. 4-oxocyclohexyl (rac) CH₃ H 2-methoxyethyl 486.4-oxocyclohexyl (rac) CH₃ H methoxymethyl 487. 4-oxocyclohexyl (S) CH₃ Hcyclobutyl 488. 4-oxocyclohexyl (S) CH₃ H 1-methylcyclopropyl 489.4-oxocyclohexyl (S) CH₃ H trifluoromethyl 490. 4-oxocyclohexyl (S) CH₃ Hdifluoromethyl 491. 4-oxocyclohexyl (S) CH₃ H 2-propyl 492.4-oxocyclohexyl (S) CH₃ H cyclopentyl 493. 4-oxocyclohexyl (S) CH₃ H2-methyl-2-propyl 494. 4-oxocyclohexyl (S) CH₃ H 2-methoxyethyl 495.4-oxocyclohexyl (S) CH₃ H methoxymethyl 496. 4-oxocyclohexyl (R) CH₃ Hcyclobutyl 497. 4-oxocyclohexyl (R) CH₃ H 1-methylcyclopropyl 498.4-oxocyclohexyl (R) CH₃ H trifluoromethyl 499. 4-oxocyclohexyl (R) CH₃ Hdifluoromethyl 500. 4-oxocyclohexyl (R) CH₃ H 2-propyl 501.4-oxocyclohexyl (R) CH₃ H cyclopentyl 502. 4-oxocyclohexyl (R) CH₃ H2-methyl-2-propyl 503. 4-oxocyclohexyl (R) CH₃ H 2-methoxyethyl 504.4-oxocyclohexyl (R) CH₃ H methoxymethyl 505. (rac)cis-3-hydroxycyclohexyl H H cyclobutyl 506. (rac)cis-3-hydroxycyclohexyl H H 1-methylcyclopropyl 507. (rac)cis-3-hydroxycyclohexyl H H trifluoromethyl 508. (rac)cis-3-hydroxycyclohexyl H H difluoromethyl 509. (rac)cis-3-hydroxycyclohexyl H H 2-propyl 510. (rac) cis-3-hydroxycyclohexylH H cyclopentyl 511. (rac) cis-3-hydroxycyclohexyl H H 2-methyl-2-propyl512. (rac) cis-3-hydroxycyclohexyl H H 2-methoxyethyl 513. (rac)cis-3-hydroxycyclohexyl H H methoxymethyl 514. (rac) trans-3- H Hcyclobutyl hydroxycyclohexyl 515. (rac) trans-3- H H 1-methylcyclopropylhydroxycyclohexyl 516. (rac) trans-3- H H trifluoromethylhydroxycyclohexyl 517. (rac) trans-3- H H difluoromethylhydroxycyclohexyl 518. (rac) trans-3- H H 2-propyl hydroxycyclohexyl519. (rac) trans-3- H H cyclopentyl hydroxycyclohexyl 520. (rac)trans-3- H H 2-methyl-2-propyl hydroxycyclohexyl 521. (rac) trans-3- H H2-methoxyethyl hydroxycyclohexyl 522. (rac) trans-3- H H methoxymethylhydroxycyclohexyl 523. (1S,3R)-3-hydroxycyclohexyl H H cyclobutyl 524.(1S,3R)-3-hydroxycyclohexyl H H 1-methylcyclopropyl 525.(1S,3R)-3-hydroxycyclohexyl H H trifluoromethyl 526.(1S,3R)-3-hydroxycyclohexyl H H difluoromethyl 527.(1S,3R)-3-hydroxycyclohexyl H H 2-propyl 528.(1S,3R)-3-hydroxycyclohexyl H H cyclopentyl 529.(1S,3R)-3-hydroxycyclohexyl H H 2-methyl-2-propyl 530.(1S,3R)-3-hydroxycyclohexyl H H 2-methoxyethyl 531.(1S,3R)-3-hydroxycyclohexyl H H methoxymethyl 532.(1S,3S)-3-hydroxycyclohexyl H H cyclobutyl 533.(1S,3S)-3-hydroxycyclohexyl H H 1-methylcyclopropyl 534.(1S,3S)-3-hydroxycyclohexyl H H trifluoromethyl 535.(1S,3S)-3-hydroxycyclohexyl H H difluoromethyl 536.(1S,3S)-3-hydroxycyclohexyl H H 2-propyl 537.(1S,3S)-3-hydroxycyclohexyl H H cyclopentyl 538.(1S,3S)-3-hydroxycyclohexyl H H 2-methyl-2-propyl 539.(1S,3S)-3-hydroxycyclohexyl H H 2-methoxyethyl 540.(1S,3S)-3-hydroxycyclohexyl H H methoxymethyl 541.(1R,3S)-3-hydroxycyclohexyl H H cyclobutyl 542.(1R,3S)-3-hydroxycyclohexyl H H 1-methylcyclopropyl 543.(1R,3S)-3-hydroxycyclohexyl H H trifluoromethyl 544.(1R,3S)-3-hydroxycyclohexyl H H difluoromethyl 545.(1R,3S)-3-hydroxycyclohexyl H H 2-propyl 546.(1R,3S)-3-hydroxycyclohexyl H H cyclopentyl 547.(1R,3S)-3-hydroxycyclohexyl H H 2-methyl-2-propyl 548.(1R,3S)-3-hydroxycyclohexyl H H 2-methoxyethyl 549.(1R,3S)-3-hydroxycyclohexyl H H methoxymethyl 550.(1R,3R)-3-hydroxycyclohexyl H H cyclobutyl 551.(1R,3R)-3-hydroxycyclohexyl H H 1-methylcyclopropyl 552.(1R,3R)-3-hydroxycyclohexyl H H trifluoromethyl 553.(1R,3R)-3-hydroxycyclohexyl H H difluoromethyl 554.(1R,3R)-3-hydroxycyclohexyl H H 2-propyl 555.(1R,3R)-3-hydroxycyclohexyl H H cyclopentyl 556.(1R,3R)-3-hydroxycyclohexyl H H 2-methyl-2-propyl 557.(1R,3R)-3-hydroxycyclohexyl H H 2-methoxyethyl 558.(1R,3R)-3-hydroxycyclohexyl H H methoxymethyl

The compounds I according to the invention can be prepared by analogy tomethods known from the literature. An important approach to thecompounds according to the invention is offered by the reaction of a2-(N-protected aminocycloalkyl)-acetaldehyde compound II with an4-piperazine-1yl-pyrimidine compound III as depicted in scheme 1.

In scheme 1, R¹, R², R^(3a), R^(3b), R⁴, R⁵ and A have theaforementioned meanings. Pg is N-protective group which can be cleavedunder mild conditions, such as methoxycar-bonyl, ethoxycarbonyl,tert-butoxycrbonyl (boc), benzyloxycarbonyl (cbz),2-trimethylsilylethoxycarbonyl (Teoc) or 9-fluorenylmethoxycaronbyl(fmoc).

In step a) of scheme 1, an aldehyde of the formula (II) is reacted witha compound of formula III under conditions of a reductive amination.Usually a mild reducing agent, e.g. a borohydride such as sodiumborohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, isused. The skilled person is familiar with the reaction conditions whichare required for a reductive amination, e.g. from Bioorganic andMedicinal Chemistry Lett. 2002, 12(5), pp. 795-798 and 12(7) pp.1269-1273.

The thus obtained compound of formula IV is deprotected in step b) andreacted in step c) with an acylating agent, e.g. an acyl halide, inparticular an acylchloride of the formula R¹—C(O)Cl, a carboxylic acidof the formula R¹—C(O)OH, a C₁-C₄-alkyl ester or an anhydride thereof,to yield the compound of the formula I.

Compounds of the formula II are well known, e.g. from WO 2008/125891, orcan be prepared by analogy to the methods described in J. Med. Chem. 43,1878 (2000)

Compounds of the formula III are well known, or can be prepared byanalogy to the methods described in WO 99/02503, WO 2004/080981,WO2004/108706, WO 2005/118558, WO 2005/118571 and WO 2009/056625.

A particular approach to compounds of the formula III is shown in scheme2 below:

In a first step, a piperazine compound V wherein Q is H or anN-protecting group is reacted with a pyrimidine compound VI wherein Z ishalogen to yield a compound of the formula III. This method is knownfrom the prior art cited in the introductory part of the application andalso from WO 99/09015 and WO 03/002543.

The preparation of the pyrimidine compounds VI is simply achieved byreacting an amidinium chloride (VIII) with a suitable β-ketoester VII toyield a 4-hydroxypyrimidine of the formula IX which can be transformedto the halo compound VI by reacting it with halogenating agent such asthionyl chloride, phosphoryl chloride, phosphoryl bromide, phosphoroustrichloride, phosphorous tribromide or phosphorous pentachloride (seescheme 3):

βB-Ketoesters VII can be simply synthesized according to the methodsdescribed in this application from the corresponding acid chloridesR⁵—COCl by reaction with meldrum's acid(2,2-dimethyl-4,6-dioxo-1,3-dioxan) according to the process asdescribed herein and in B. Trost et al., Journal of the AmericanChemical Society (2002), 124(35):10396-10415; Paknikar, S. K. et al.,Journal of the Indian Institute of Science (2001), 81(2):175-179; andBrummell, David G. et al., Journal of Medicinal Chemistry (2001),44(1):78-93.

The N-oxides of compound I may be prepared from the compounds of formulaI according to conventional oxidation methods, for example by treatingsaid compounds with an organic peracid; such as metachloroperbenzoicacid or 3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11),1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents; suchas hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7),1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxidesor to a mixture of different N-oxides, which can be separated byconventional methods; such as chromatography.

The reactions are usually performed in an organic solvent, includingaprotic organic solvent, e.g. substituted amides, lactames and ureas;such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetramethyl urea, cyclic ethers; such as dioxane, tetrahydrofurane,halogenated hydrocarbons; such as dichloromethane, and mixtures thereofas well as mixtures thereof with C₁-C₆-alkanols and/or water.

The reactions described above will be usually performed at temperaturesranging from −10° C. to 100° C., depending on the reactivity of the usedcompounds.

The reaction mixtures are worked up in a conventional way, e.g. bymixing with water, separating the phases and, where appropriate,purifying the crude products by chromatography. The intermediates andfinal products in some cases result in the form of colorless or palebrownish, viscous oils which are freed of volatiles or purified underreduced pressure and at moderately elevated temperature. If theintermediates and final products are obtained as solids, thepurification can also take place by recrystallization or digestion.

Due to their capability of selectively binding to the dopamine D3receptor at low concentrations, in particular at least partiallyantagonizing the Dopamine D3 receptor, the compounds of the formula I,their N-oxides and their prodrugs and the pharmaceutically acceptablesalts thereof, are particularly suitable for treating disorders orconditions, which can be treated by modulation of the dopamine D3receptor, in particular by at least partially antagonizing the DopamineD3 receptor. The terms “treating” and “treatment” in terms of thepresent invention have to be understood to include both curativetreatment of the cause of a disease or disorder, the treatment of thesymptoms associated with a disease or disorder, i.e. controlling thedisease or disorder or ameliorating the conditions or symptomsassociated with a disease or disorder, and prophylactic treatment, i.e.a treatment for reducing the risk of a disease or disorder.

Neurological and psychiatric disorders or conditions which can betreated by dopamine D3 receptor ligands, including curative treatment,control or amelioration and prophylaxis, include CNS disorders, inparticular schizophrenia, depression, motivation disturbances, bipolardisorders, cognitive dysfunctions, in particular cognitive dysfunctionsassociated with schizophrenia, cognitive dysfunctions associated withdementia (Alzheimer's disease), Parkinson's disease, anxiety,dyskinesia, in particular L-DOPA induced dyskinesia (LID), especiallydyskinesia associated with L-DOPA therapy to treat Parkinson's disease,substance-related disorders, especially substance use disorder,substance tolerance conditions associated with substance withdrawal,attention deficit disorders with or without hyperactivity, eatingdisorders, and personality disorder as well as pain. Disorders orconditions which can be treated by modulating the dopamine D3 receptor,including curative treatment, control or amelioration and prophylaxis,also include treatment of disturbances of kidney function, i.e. renalfunction disorders, in particular kidney function disturbances which arecaused by diabetes such as diabetes mellitus, also termed as diabeticnephropathy.

Thus, the invention relates to the use of compounds of formula I, theirN-oxides and their prodrugs and the pharmaceutically acceptable saltsthereof, for treatment of disorders or conditions, which can be treatedby modulation of the dopamine D3 receptor, i.e. the invention relates tothe use of such compounds for curative treatment of such a disease ordisorder, controlling such a disease or disorder, ameliorating thesymptoms associated with such a disease or disorder and reducing therisk for such a disease or disorder.

The present invention also relates to a method for the treatment of amedical disorder, selected from neurological and psychiatric disorderswhich can be treated by modulation of the dopamine D3 receptor, saidmethod comprising administering an effective amount of at least onecompound, selected from the group of compounds of formula I, theirN-oxides, their prodrugs and the pharmaceutically acceptable saltsthereof, to a mammal in need thereof. The present invention also relatesto a method for the treatment of renal function disorders, in particularkidney function disturbances which are caused by diabetes such asdiabetes mellitus, said method comprising administering an effectiveamount of at least one compound, selected from the group of compounds offormula I, their N-oxides, their prodrugs and the pharmaceuticallyacceptable salts thereof, to a mammal in need thereof.

The present invention in particular relates to:

-   -   a method for treating, controlling, ameliorating or reducing the        risk of schizophrenia in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of cognitive disturbances associated with schizophrenia in        a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of depression in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of bipolar disorders in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with substance abuse disorders in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with eating disorders in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of cognitive disturbances associated with Alzheimer's        disease in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of anxiety in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of Parkinson's disease in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of disturbances associated with Parkinson's disease in a        mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of renal function disorders, in particular diabetic        nephropathy in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of disturbances associated with renal function disorders,        in particular diabetic nephropathy, in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of dyskinesia, in particular L-DOPA induced dyskinesia        (LID), especially LID associated with treatment of Parkinson's        disease, more especially LID associated with long-term treatment        of Parkinson's disease;    -   and a method for treating, ameliorating or reducing the risk of        pain in a mammalian;

which methods comprising administering an effective amount of at leastone compound, selected from the group of compounds of formula I, theirN-oxides, their prodrugs and the pharmaceutically acceptable saltsthereof, to a mammal in need thereof. The subject treated in the presentmethods is generally a mammal, preferably a human being, male or female,in whom modulation of dopamine D3 receptor is desired. The terms“effective amount” and “therapeutically effective amount” mean theamount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doc-tor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes, wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe disorders described herein, but does not necessarily indicate atotal elimination of all disorder symptoms, as well as the prophylactictherapy of the mentioned conditions, particularly in a patient who ispre-disposed to such disease or disorder. The term “composition” as usedherein is intended to encompass a product comprising the specifiedingredients in the specified amounts, as well as any product whichresults, directly or indirectly, from combination of the specifiedingredients in the specified amounts. Such term in relation topharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s) thatmake up the carrier, as well as any product which results, directly orindirectly, from combination, complexation or aggregation of any two ormore of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of and or “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need of treatment.

A preferred embodiment of the present invention provides a method fortreating schizophrenia, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating cognitive disturbances associated with schizophrenia,comprising: administering to a patient in need thereof an effectiveamount of at least one compound, selected from the group of compounds offormula I, their N-oxides, their prodrugs and the pharmaceuticallyacceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating dyskinesia comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating L-DOPA induced dyskinesia (LID), in particular LIDassociated with treatment of Parkinson's disease, especially LIDassociated with long-term treatment of Parkinson's disease.comprising:administering to a patient in need thereof an effective amount of atleast one compound, selected from the group of compounds of formula I,their N-oxides, their prodrugs and the pharmaceutically acceptable saltsthereof.

At present, the fourth edition of the Diagnostic and Statistical Manualof Mental Disorders (DSM-IV) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool including schizophreniaand other psychotic disorders. These include: disorders having psychoticsymptoms as the defining feature. The term psychotic refers todelusions, prominent hallucinations, disorganized speech, disorganizedor catatonic behavior. The disorder includes: paranoid, disorganized,catatonic, undif-ferentiated, and residual schizophrenia,schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition, substance-induced psychoticdisorder, and psychotic disorder not otherwise specified. The skilledartisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, and particular schizophrenia, and that these systems evolvewith medical scientific progress. Thus, the term “schizophrenia” isintended to include like disorders that are described in otherdiagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, comprising: administering to apatient in need thereof an effective amount of at least one compound,selected from the group of compounds of formula I, their N-oxides, theirprodrugs and the pharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof. At present, the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) (1994, American Psychiatric Association, Washington, D.C.),provides a diagnostic tool including anxiety and related disorders.These include: panic disorder with or without agoraphobia, agoraphobiawithout history of panic disorder, specific phobia, social phobia,obsessive-compulsive disorder, post-traumatic stress disorder, acutestress disorder, generalized anxiety disorder, anxiety disorder due to ageneral medical condition, substance-induced anxiety disorder andanxiety disorder not otherwise specified. As used herein the term“anxiety” includes treatment of those anxiety disorders and relateddisorder as described in the DSM-IV. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders, and particularanxiety, and that these systems evolve with medical scientific progress.Thus, the term “anxiety” is intended to include like disorders that aredescribed in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating depression, comprising: administering to a patient in needthereof an effective amount of at least one compound, selected from thegroup of compounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof. At present, the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) (1994, American Psychiatric Association, Washington, D.C.),provides a diagnostic tool including depression and related disorders.Depressive disorders include, for example, single episodic or recurrentmajor depressive disorders, and dysthymic disorders, depressiveneurosis, and neurotic depression; melancholic depression includinganorexia, weight loss, insomnia and early morning waking, andpsychomotor retardation; atypical depression (or reactive depression)including increased appetite, hypersomnia, psychomotor agitation orirritability, anxiety and phobias; seasonal affective disorder; orbipolar disorders or manic depression, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder. As used herein the term“depression” includes treatment of those depression disorders andrelated disorder as described in the DSM-1V.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, especially substancedependence, substance abuse, substance tolerance, and substancewithdrawal, comprising: administering to a patient in need thereof aneffective amount at least one compound, selected from the group ofcompounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof. At present, the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) (1994, American Psychiatric Association, Washington, D.C.),provides a diagnostic tool including disorders related to taking a drugof abuse (including alcohol), to the side effects of a medication, andto toxin exposure. Substances include alcohol, amphetamine and similarlyacting sympathomimetics, caffeine, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine (PCP) or similarly actingarylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also,polysubstance dependence and other unknown substance-related disordersare included. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders, and particular substance-relateddisorders, and that these systems evolve with medical scientificprogress. Thus, the term “substance-related disorder” is intended toinclude like disorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating Parkinson's disease and the symptoms and disturbancesassociated with Parkinson's disease: comprising: administering to apatient in need thereof an effective amount at least one compound,selected from the group of compounds of formula I, their N-oxides, theirprodrugs and the pharmaceutically acceptable salts thereof.

In another preferred embodiment, the present invention provides a methodfor treating renal function disorders, in particular diabeticnephropathy: comprising administering to a patient in need thereof aneffective amount at least one compound, selected from the group ofcompounds of formula I, their N-oxides, their prodrugs and thepharmaceutically acceptable salts thereof.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require modulation of the dopamine D3 receptoran appropriate dosage level will generally be about 0.01 to 500 mg perkg patient body weight per day which can be administered in single ormultiple doses. Preferably, the dosage level will be about 0.1 to about250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.A suitable dosage level may be about 0.01 to 250 mg/kg per day, about0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within thisrange the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.For oral administration, the compositions are preferably provided in theform of tablets containing 1.0 to 1000 milligrams of the activeingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0,100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. When treating, preventing,controlling, ameliorating, or reducing the risk of neurological andpsychiatric disorders or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 milligram to about 100 milligram perkilogram of animal body weight, preferably given as a single daily doseor in divided doses two to six times a day, or in sustained releaseform. For most large mammals, the total daily dosage is from about 1.0milligrams to about 1000 milligrams, preferably from about 1 milligramto about 500 milligrams, in the case of a 70 kg adult human, the totaldaily dose will generally be from about 3 milligrams to about 350milligrams. This dosage regimen may be adjusted to provide the optimaltherapeutic response. It will be understood, however, that the specificdose level and frequency of dosage for any particular patient may bevaried and will depend upon a variety of factors including the activityof the specific compound employed, the metabolic stability and length ofaction of that compound, the age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

The compounds of the present invention may be administered byconventional routes of administration, including parenteral (e.g.,intramuscular, intrapentoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), oral, byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration.

The compounds according to the present invention are further useful in amethod for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of Formula I. When a compound of formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of formula I, an N-oxide, aprodrug or a salt thereof. The above combinations include combinationsof a compound of the present invention not only with one other activecompound, but also with two or more other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The present invention also relates to pharmaceutical compositions (i.e.medica-ments) which comprise at least one compound of the presentinvention and, where appropriate, one or more suitable excipients.

These excipients/drug carriers are chosen according to thepharmaceutical form and the desired mode of administration.

The compounds of the present invention can be used to manufacturepharmaceutical compositions for parenteral (e.g., intramuscular,intrapentoneal, intravenous, ICV, intracisternal injection or infusion,subcutaneous injection, or implant), oral, sublingual, intratracheal,intranasal, topical, transdermal, vaginal or rectal administration, andbe administered to animals or humans in unit dose forms, mixed withconventional pharmaceutical carriers, for the prophylaxis or treatmentof the above impairments or diseases.

In the pharmaceutical compositions, the at least one compound of thepresent invention may be formulated alone or together with furtheractive compounds, in suitable dosage unit formulations containingconventional excipients, which generally are non-toxic and/orpharmaceutically acceptable. Carriers or excipients can be solid,semisolid or liquid materials which serve as vehicles, carriers ormedium for the active compound. Suitable excipients are listed in thespecialist medicinal monographs. In addition, the formulations cancomprise pharmaceutically acceptable carriers or customary auxiliarysubstances, such as glidants; wetting agents; emulsifying and suspendingagents; pre-servatives; antioxidants; antiirritants; chelating agents;coating auxiliaries; emulsion stabilizers; film formers; gel formers;odor masking agents; taste corrigents; resin; hy-drocolloids; solvents;solubilizers; neutralizing agents; diffusion accelerators; pigments;quaternary ammonium compounds; refatting and overfatting agents; rawmaterials for ointments, creams or oils; silicone derivatives; spreadingauxiliaries; stabilizers; sterilants; suppository bases; tabletauxiliaries, such as binders, fillers, glidants, disintegrants orcoatings; propellants; drying agents; opacifiers; thickeners; waxes;plasticizers and white mineral oils. A formulation in this regard isbased on specialist knowledge as described, for example, in Fiedler, H.P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzendeGebiete [Encyclopedia of auxiliary substances for pharma-cy, cosmeticsand related fields], 4^(th) edition, Aulendorf:ECV-Editio-Kantor-Verlag, 1996.

Suitable unit dose forms include forms for oral administration, such astablets, gelatin capsules, powders, granules and solutions orsuspensions for oral intake, forms for sublingual, buccal, intratrachealor intranasal administration, aerosols, implants, forms of subcutaneous,intramuscular or intravenous administration and forms of rectaladministration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

If a solid composition is prepared in the form of tablets, the mainingredient is mixed with a pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets may be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display aprolonged or delayed activity and in order to release a predeterminedamount of the active basic ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and taking up the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may comprise active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloring.

The water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agentssuch as polyvinylpyrrolidones, and sweeteners or taste improvers.

Rectal administration is achieved by the use of suppositories which areprepared with binders which melt at the rectal temperature, for examplecocobutter or polyethylene glycols. Parenteral administration iseffected by using aqueous suspensions, isotonic salt solutions orsterile and injectable solutions which comprise pharmacologicallysuitable dispersants and/or wetting agents, for example propylene glycolor polyethylene glycol.

The active basic ingredient may also be formulated as microcapsules orliposomes/centrosomes, if suitable with one or more carriers oradditives.

In addition to the compounds of the general formula I, their prodrugs,their N-oxides, their tautomers, their hydrates or theirpharmaceutically suitable salts, the compositions of the invention maycomprise further active basic ingredients which may be beneficial forthe treatment of the impairments or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active basic ingredients arepresent together, where at least one thereof is a compound of theinvention.

When producing the pharmaceutical compositions, the compounds accordingto the invention are optionally mixed or diluted with one or morecarriers.

The following examples are intended for further illustration of thepresent invention.

The compounds were either characterized via ¹H NMR ind₆-dimethylsulfoxid, deuteromethanol or deuterochloroform, if not statedotherwise, on a 400 MHz, 500 MHz, or 600 MHz NMR instrument (BrukerAVANCE), or by mass spectrometry, generally recorded via HPLC-MS in afast gradient on C18-material (electrospray-ionisation (ESI) mode), ormelting point.

The magnetic nuclear resonance spectral properties (NMR) refer to thechemical shifts (δ) expressed in parts per million (ppm). The relativearea of the shifts in the 1H NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift, as regards multiplicity, is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.) and multiplet(m).

Abbreviations:

AcOH acetic acidBoc tert-butyloxycarbonylDCE 1,2-dichloroethaneDCM dichloromethaneEA ethyl acetateEtOH ethanolhr hourMeOH methanolNaOMe sodium methoxideMeOD deuteromethanolPE petroletherpre-TLC preparative thin layer chromatographyRT retention timeTHF tetrahydrofuran

Intermediates I. Pyrimidyl-Piperazine Building Block I.12-tert-Butyl-4-(2-methoxy-ethyl)-6-piperazin-1-yl-pyrimidine I.1.15-Methoxy-3-oxo-pentanoic acid methyl ester

To a solution of 3-methoxy propionyl chloride (51.7 g, 359 mmol) andpyridine (87 mL, 1077 mmol) in DCM (400 mL), dimedon (44 g, 359 mmol)was added dropwise at 0° C. to 10° C. The reaction mixture was stirredovernight at room temperature, 1 N HCl (400 mL) was added, extractedwith DCM (500 mL×3). The organic layer was washed with water, dried overNa₂SO₄, filtered, and concentrated to dryness. The oily residue wasdissolved in MeOH (400 mL) and refluxed for 2 hrs. The reaction mixturewas concentrated to dryness. The residue was purified by silica gelcolumn (PE:EA=15:1) to give the title compound (27 g, 47.0% yield) aswhite oil.

¹H NMR (400 MHz CDCl₃): δ 3.72 (s, 3H), 3.65-3.62 (m, 2H), 3.49 (s, 2H),3.31 (s, 3H), 2.78-2.75 (m, 2H).

I.1.2 2-tert-Butyl-6-(2-methoxy-ethyl)-pyrimidin-4-ol

5-Methoxy-3-oxo-pentanoic acid methyl ester (27 g, 169 mmol) andtert-butyl amidinium hydrochloride (18.57 g, 185 mmol) were dissolved inMeOH (200 mL); sodium methanolate (27.3 g, 506 mmol) was added inportions to the solution at 10° C. The reaction mixture was then stirredat room temperature overnight. The reaction mixture was concentrated tohalf the volume, filtered, the filtrate was acidified with 1 N HCl topH=5, the precipitate was collected by filtration, which was dried underhigh vacuum to give the title compound (20 g, 56% yield) as white oil.

¹H NMR (400 MHz CDCl₃): δ 11.91 (s, 1H), 6.19 (s, 1H), 3.73-3.71 (m,2H), 3.34 (s, 3H), 2.79-2.75 (m, 2H), 1.37 (s, 9H).

I.1.3 2-tert-Butyl-4-chloro-6-(2-methoxy-ethyl)-pyrimidine

To a solution of 2-tert-butyl-6-(2-methoxy-ethyl)-pyrimidin-4-ol (20 g,95 mmol) in toluene (200 mL) and DMF (2 mL) was added dropwise POCl₃(36.5 g, 238 mmol) in an ice bath. The mixture was stirred for 3 hrs atroom temperature. The reaction mixture was poured into water, extractedwith DCM (400 mL×3). The organic layer was dried over Na₂SO₄ andconcentrated to give the title compound (20 g, 92% yield) as a yellowoil.

¹H NMR (400 MHz CDCl₃): δ 7.02 (s, 1H), 3.78-3.75 (m, 2H), 3.33 (s, 3H),2.96-2.93 (m, 2H), 1.36 (s, 9H).

I.1.4 2-tert-Butyl-4-(2-methoxy-ethyl)-6-piperazin-1-yl-pyrimidine

A solution of piperazine (45.2 g, 525 mmol) in ethanol (300 mL) washeated to reflux. A solution of2-tert-butyl-4-chloro-6-(2-methoxy-ethyl)-pyrimidine (20 g, 87 mmol) inethanol (50 mL) was added dropwise to the above solution. The solutionwas refluxed for another 3 hrs, cooled to room temperature. Then waterwas added and the organic layer was extracted with EA (400 mL×3). To theorganic layer was added 5% citric acid (1 L), separated, and the aqueouslayer was collected and adjusted to alkaline pH>8 with 2 N NaOH. Thealkaline aqueous layer was extracted with EA (400 mL×3), and the organicphase was dried over Na₂SO₄, filtered and concentrated to give the titlecompound (20 g, 82% yield) as a yellow oil.

¹H NMR (CDCl₃ 400 MHz): δ 6.17 (s, 1H), 3.76-3.73 (m, 2H), 3.60-3.57 (m,4H), 3.33 (s, 3H), 2.93-2.90 (m, 4H), 2.83-2.80 (m, 2H), 1.72-1.70 (m,1H), 1.31 (s, 9H).

LC-MS (ESI): m/z 279 (M+H)⁺.

I.2 2-tert-butyl-4-cyclobutyl-6-(piperazin-1-yl)pyrimidine I.2.12-tert-butyl-6-cyclobutyl-pyrimdin-4-ol

A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (4.3 g, 27.53 mmol)and 2,2-dimethylpropanamidine (2.3 g, 22.10 mmol) was stirred in dryMeOH (50 mL) and NaOMe (5.0 g, 92 mmol) was added in portions at 10° C.The suspension was stirred at room temperature overnight. The reactionmixture was concentrated to roughly half of the volume and filtered. Thefiltrate was extracted with water and DCM. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was stirred with acetone and theprecipitate collected, dried under vacuum to give the title compound(3.15 g, 15.27 mmol, 66%).

LC-MS (ESI): m/z 207 (M+H)⁺, TR: 0.864 min.

I.2.2 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine

2-tert-butyl-6-cyclobutyl-pyrimdin-4-ol (3.15 g, 15.27 mmol) wasdissolved in toluene (25 ml)/DMF (0.3 ml). POCl₃ (3.5 mL, 38 mmol) wasadded dropwise at 10° C. The resulted solution was stirred at roomtemperature for 3 h then poured into water, extracted with DCM. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated underreduced pressure to give the title compound (3.28 g, 97%). The crudematerial was used without further purification for the next step.

LC-MS: m/z=225.0 (M+H)⁺, RT: 1.186 min

I.2.3 2-tert-butyl-4-cyclobutyl-6-(piperazin-1-yl)pyrimidine

piperazine (7.54 g, 87.57 mmol) was dissolved in EtOH,2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (3.28 g, 14.60 mmol) wasadded dropwise at 80° C. over 10 min. The solution was refluxedovernight and then concentrated under reduced pressure. The residue wasdissolved in EtOAc, washed with water and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the titlecompound (3.5 g, 87%).

LC-MS: m/z=275.0 (M+H), RT: 0.564 min

II. Aldehyde Building Block II.1 tert-butylN-[3-(2-oxoethyl)cyclobutyl]carbamate II.1.1(3-tert-Butoxycarbonylamino-cyclobutylidene)-acetic acid methyl ester

To a solution of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester (5.6g, 30 2 mmol) in anhydrous toluene (100 mL) was added methyl(triphenylphosphoranylidene)acetate (10.7 g, 45.4 mmol) and heated toreflux overnight under N₂. After cooling to room temperature, themixture was poured into water and extracted with EA. The organic phasewas dried over Na₂SO₄, concentrated under reduced pressure to give aresidue, which was purified by column chromatography on silica gel(eluted with PE:EA=20:1) to give the title compound (7 g, yield 96%) asa white solid.

¹H NMR (400 MHz, CDCl₃): δ 5.71 (s, 1H), 4.86 (br, 1H), 4.25 (br, 1H),3.70 (s, 3H), 3.60 (br, 1H), 3.23-3.18 (br, 1H), 2.97-2.92 (br, 1H),2.79-2.73 (br, 1H), 1.46 (s, 9H).

II.1.2 (3-tert-Butoxycarbonylamino-cyclobutyl)-acetic acid methyl ester

To a solution of (3-tert-Butoxycarbonylamino-cyclobutylidene)-aceticacid methyl ester (7 g, 29 mmol) in methanol (100 mL) was added Pd/C (5g) and stirred at room temperature under H₂ balloon overnight. After TLCshowed the reaction was completed, the mixture was filtered over Celite.The filtrate was concentrated under reduced pressure to give the titlecompound (7 g, yield 99%) as a white solid, which was used for the nextstep directly without further purification.

II.1.3 3-(2-Hydroxy-ethyl)-cyclobutyl]-carbamic acid tert-butyl ester

To a solution of (3-tert-butoxycarbonylamino-cyclobutyl)-acetic acidmethyl ester (7 g, 28.8 mmol) in anhydrous THF (100 mL) was added LiAlH₄(2.18 g, 57.5 mmol) dropwise at 0° C. and the mixture was stirred at 0°C. for 2 hrs. The mixture was quenched with water (2 mL), NaOH solution(0.5 N, 2 mL) and water (2 mL), filtered and extracted with EA. Theorganic phase was washed by brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound (5.7 g,yield 92%) as a white solid, which was used for next step directlywithout further purification.

II.1.4 tert-butyl N-[3-(2-oxoethyl)cyclobutyl]carbamate

To a solution of 3-(2-hydroxy-ethyl)-cyclobutyl]-carbamic acidtert-butyl ester (5.2 g, 24.1 mmol) in anhydrous DCM (100 mL) was addedDess-Martin periodinane (20.5 g, 48.3 mmol) and stirred at roomtemperature for 5 hrs. The mixture was quenched with Na₂S₂O₃ solution,extracted with DCM. The organic phase was concentrated under reducedpressure to give a residue, which was purified by column chromatographyon silica gel (eluted with PE:EA=5:1) to give the title compound (2.7 g,yield 52%) as an oily liquid.

II.2 tert-butyl trans-4-(2-oxoethyl)cyclohexylcarbamate

Commercially available

II.3 tert-butyl cis-4-(2-oxoethyl)cyclohexylcarbamate

Commercially available

III. EXAMPLES Example 1

trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 1; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis configuration)

1.1 tert-butyltrans-N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]carbamate

A mixture of 2-tert-butyl-4-cyclobutyl-6-(piperazin-1-yl)pyrimidine(7.16 g, 26.1 mmol) and tert-butyltrans-4-(2-oxoethyl)cyclohexylcarbamate (6 g, 24.86 mmol) in DCE (100ml) was stirred at room temperature for 10 min. AcOH and sodiumtriacetox-yhydroborate (7.90 g, 37.3 mmol) were added. After 4 h, waterwas added. The aqueous layer was extracted with methylene chloride (3×50mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give thetitle compound as a yellow oil of (11.2 g, 21.29 mmol, 86% yield) whichwas used next step without purification.

LC-MS: M/z=500.0 (M+H)⁺, RT: 0.67 min.

1.2Trans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine

Tert-butylN-[trans-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]carbamate(11.20 g, 22.41 mmol) was dissolved in HCl/ethyl acetate (150 mL). Theresulting solution was stirred at about 25° C. for 16 h. Solvent wasremoved under reduced pressure to provide the title compound (8.9 g,21.16 mmol, 94% yield) as a colorless solid.

LC-MS: M/z=400.0 (M+H)⁺, RT: 0.52 min

1.3trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide

Trans-4-hydroxycyclohexanecarboxylic acid (1,991 g, 13.81 mmol) wasadded to a solution oftrans-4-(2-(4-(2-(tert-butyl)-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl)ethyl)cyclohexanamine(4.6 g, 11.51 mmol) in dichloromethane. HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate, 5.25 g, 13.8 mmol) and diisopropylethylamine (6.03mL, 34.5 mmol) were added and the mixture stirred at room temperaturefor 14 h. The solvent was evaporated and the residue partitioned betweendichloromethane and water. The aqueous phase was extracted several timeswith dichloromethane. The combined organic layers were washed twice with5% aqueous sodium bicarbonate solution and twice with saturated aqueoussodium chloride solution, dried over sodium sulfate, filtered andevaporated to dryness. Purification via silica gel chromatography (330 gReveleris NP cartridge) with di-chloromethane/methanol (0-80%) as eluentyielded 6.05 g of the title compound.

LC-MS: m/z 526.4 (M+H)⁺, RT: 2.54 min.

¹H-NMR (CDCl₃, 400 MHz): 1.04-1.08 (m, 4H), 1.13-1.25 (m, 3H), 1.34 (s,9H), 1.43-1.63 (m, 5H), 1.74-1.79 (m, 2H), 1.87-2.06 (m, 9H), 2.25-2.37(m, 4H), 2.42 (m, 2H), 2.53 (bs, 4H), 3.43-3.46 (m, 1H), 3.59-3.67 (m,2H), 3.67 (bs, 4H), 5.23 (d, J=8.4 Hz, 1H), 6.12 (s, 1H).

The compounds of the examples 2 to 44 were prepared following the sameway shown above

Example 2

trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 2; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H, and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 3

trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 3; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 4

cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 4; compound of the formula I, where R¹ iscis-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 5

Cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 5; compound of the formula I, where R¹ iscis-4-hydroxycyclohexyl; m is 2, n is 2, R²═H, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 6

trans-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 6, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 7

Trans-N-[trans-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide;2,2,2-trifluoroacetic acid (compound 7, compound of the formula I, whereR¹ is trans-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 8

trans-N-[cis-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide;2,2,2-trifluoroacetic acid (compound 8, compound of the formula I, whereR¹ is trans-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 9

Trans-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide(compound 9; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 1, n is 1 and the radical R¹—C(═O)—NH,R²═H and the radical R² have cis-configuration)

Example 10

Trans-N-[cis-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide(compound 10; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 11

N-[trans-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide(compound 11; compound of the formula I, where R¹ is4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radical R¹—C(═O)—NHand the radical R² have cis-configuration)

Example 12

Cis-N-[cis-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide(compound 12; compound of the formula I, where R¹ iscis-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 13

Cis-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide(compound 13; compound of the formula I, where R¹ iscis-3-hydroxycyclobutyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 14

Cis-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;2,2,2-trifluoroacetic acid (compound 14; compound of the formula I,where R¹ is cis-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 15

Cis-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;2,2,2-trifluoroacetic acid (compound 15; compound of the formula I,where R¹ is cis-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have trans-configuration)

Example 16

Cis-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide;2,2,2-trifluoroacetic acid (compound 16; compound of the formula I,where R¹ is cis-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 17

cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide(compound 17; compound of the formula I, where R¹ iscis-4-hydroxycyclohexyl; m is 1, n is 1, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 18

cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide(compound 18; compound of the formula I, where R¹ iscis-3-hydroxycyclobutyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 19

N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide(Compound 19; compound of the formula I, where R¹ is3-hydroxy-3-trifluoromethylcyclobutyl; m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 20

trans-N-[trans-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 20; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 21

trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 21; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 22

trans-N-[cis-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 22; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 23

Trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 23; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 24

trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide(compound 24; compound of the formula I, where R¹ istrans-4-methoxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 25

N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide(compound 25; compound of the formula I, where R¹ is3-hydroxy-3-trifluoromethylcyclobutyl, m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 26

N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide(compound 26; compound of the formula I, where R¹ is3-hydroxy-3-trifluoromethylcyclobutyl, m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have trans-configuration)

Example 27

N-[4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 27; compound of the formula I, where R¹ is4-hydroxycyclohexyl; m is 2, n is 2, R²═H)

Example 28

Trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 28; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 29

N-[4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 29; compound of the formula I, where R¹ is4-hydroxycyclohexyl; m is 2, n is 2, R²═H)

Example 30

Trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 30; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 31

N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 31; compound of the formula I, where R¹ is4-hydroxycyclohexyl; m is 2, n is 2, R²═H)

Example 32

Trans-N-[trans-4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 32; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 33

N-[4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 33; compound of the formula I, where R¹ is4-hydroxycyclohexyl; m is 2, n is 2, R²═H)

Example 34

trans-N-[trans-4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 34; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 35

trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 35; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 36

trans-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 36; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

Example 37

trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 37; compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 38

trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide;2,2,2-trifluoroacetic acid (compound 38; compound of the formula I,where R¹ is trans-3-hydroxycyclobutyl; m is 2, n is 2, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 39

trans-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide;2,2,2-trifluoroacetic acid (compound 39; compound of the formula I,where R¹ is trans-3-hydroxycyclobutyl; m is 1, n is 1, R²═H and theradical R¹—C(═O)—NH and the radical R² have cis-configuration)

Example 40

cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide(compound 40; compound of the formula I, where R¹ iscis-3-hydroxycyclobutyl; m is 2, n is 2, R²═H and the radicalR¹—C(═O)—NH and the radical R² have cis-configuration)

Example 41

Trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide(compound 41, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H, R^(3b) is (S) methyland the radical R¹—C(═O)—NH and the radical R² have cis-configuration)

LCMS: m/z 528.4 (M+H)

¹H-NMR (CDCl₃, 400 MHz): δ: 6.1 (s, 1H), 5.23 (d, 1H), 4.55 (m, 1H),4.15 (m, 1H), 3.7 (m, 1H), 3.62 (m, 1H), 3.13 (m, 1H), 2.9 (m, 1H), 2.78(m, 2H), 2.4 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.85-2.1 (several m,10H), 1.8 (m, 2H), 1.2-1.6 (broad, several m, 5H), 1.55 (m, 2H), 1.4 (m,2H), 1.3 (s, 9H), 1.25 (m, 6H), 1.1 (m, 3H).

Example 42

N-[3-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclobutyl]-trans-4-hydroxy-cyclohexanecarboxamide(compound 42, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 1, n is 1, R²═H, R^(3b) is (S)-methyland the radical R¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 500.3 (M+H)

¹H-NMR (CDCl₃, 400 MHz): δ: 6.08 (s, 1H), 5.5 (d, 1H), 4.55 (m, 1H),4.25 (m, 1H), 4.15 (m, 1H), 3.6 (m, 1H), 3.12 (m, 1H), 2.88 (m, 1H),2.7-2.85 (m, 2H), 2.55 (m, 2H), 2.3 (m, 1H), 2.2 (m, 2H), 1.8-2.1(several m, 7H), 1.35-1.7 (several m, 9H), 1.33 (s, 9H), 1.28 (m, 2H),1.2 (d, 6H).

Example 43

Cis-N-[4-[2-[4-(2tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide(compound 43, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 514.5 (M+H)

¹H-NMR (CDCl₃, 600 MHz): δ: 6.14 (s, 1H), 5.49 (d, J=7.5 Hz, 1H),3.97-4.05 (m, 1H), 3.60-3.69 (m, 5H), 2.81 (spt, J=6.9 Hz, 1H), 2.52 (t,J=5.1 Hz, 4H), 2.40 (dd, J=8.8, 6.6 Hz, 2H), 2.03-2.1 (m, 2H), 1.98-1.99(m, 1H), 1.87-1.94 (m, 2H), 1.59-1.65 (m, 5H), 1.57 (d, J=3.4 Hz, 1H),1.55 (d, J=3.2 Hz, 1H), 1.48-1.54 (m, 3H), 1.45-1.47 (m, 1H), 1.33 (s,9H), 1.28-1.34 (m, 1H), 1.23 (d, J=6.8 Hz, 6H), 1.18-1.26 (m, 2H).

Example 44

Cis-N-[4-[2-[(3S)-4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide(compound 44, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl; m is 2, n is 2, R²═H, R^(3b) is (S) methyl,and the radical R¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 536.5 (M+H)

¹H-NMR (CD₃OD, 400 MHz): δ: 7.7 (d, 1H), 6.7 (s, 1H), 6.47 (t, 1H,CHF₂), 4.7 (m, 1H), 4.3 (m, 1H), 3.85 (m, 1H), 3.5 (m, 1H), 3.3 (m, 2H),3.2 (m, 1H), 3.05 (m, 1H), 2.95 (m, 1H), 2.4 (m, 1H), 2.23 (m, 2H), 2.1(m, 1H), 2.03 (m, 2H), 1.8 (m, 2H), 1.2-2.7 (several m, 13H), 1.35 (s,9H), 1.28 (d, 3H), 0.92 (m, 1H).

Example 45

Trans-N-[(1S)-3-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclopentyl]-4-hydroxy-cyclohexanecarboxamide_(compound45, compound of the formula I, where R¹ is trans-4-hydroxycyclohexyl, mis 2, n is 1, R²═H, R^(3a) is H, R^(3b) is (S) methyl, A is CH₂, R⁴ istert.butyl, R⁵ is isopropyl, and the radical R¹—C(═O)—NH and the radicalR² have trans-configuration)

LCMS: m/z 514.4 (M+H)

Example 46

Trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide(compound 46, compound of the formula I, where R¹ istrans-4-hydroxycyclohexyl, m is 2, n is 2, R²═H, R^(3a) is H, R^(3b) is(S) methyl, A is CH₂, R⁴ is tert.butyl, R⁵ is isopropyl, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 528.4 (M+H)

¹H NMR (CHLOROFORM-d, 600 MHz): δ=6.1 (s, 1H), 5.5 (d, 1H), 4.55 (m,1H), 4.15 (m, 1H), 4.0 (m, 1H), 3.65 (m, 1H), 3.12 (m, 1H), 2.9 (m, 1H),2.8 (m, 2H), 2.4 (m, 1H), 2.3 (m, 1H), 2.18 (m, 1H), 1.98-2.1 (severalm, 4H), 1.92 (m, 1H), 1.4-1.7 (several m, 14H), 1.32 (s, 9H), 1.3 (m,2H), 1.22 (d, 6H), 1.2 (m, 2H).

Example 47

Trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-3-methoxy-cyclobutanecarboxamide(compound 48, compound of the formula I, where R¹ istrans-3-methoxycyclobutyl, m is 2, n is 2, R²═H, R^(3a) is H, R^(3b) is(S) methyl, A is CH₂, R⁴ is tert.butyl, R⁵ is isopropyl, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 514.4 (M+H)

¹H-NMR (CDCl₃, 600 Hz): δ [ppm] 6.1 (s, 1H), 5.2 (d, 1H), 4.56 (broad,1H), 4.13 (m, 1H), 3.72 (m, 1H), 3.24, (s, 3H), 3.15 (m, 1H), 2.90 (m,1H), 2.82 (m, 2H), 2.47 (m, 2H), 2.39 (m, 1H), 2.29 (m, 1H), 2.17 (m,3H), 2.04 (m, 1H), 1.98 (m, 2H), 1.89 (m, 2H), 1.44 (m, 2H), 1.34 (s,9H), 1.2-1.35 (m, 11H), 1.08 (m, 4H).

Example 48

Trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxycyclobutanecarboxamide(compound 48, compound of the formula I, where R¹ istrans-3-hydroxycyclobutyl, m is 2, n is 2, R²═H, R^(3a) is H, R^(3b) is(S) methyl, A is CH₂, R⁴ is tert.butyl, R⁵ is isopropyl, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

The title compound was prepared by O-demethylation of the corresponding3-methoxy-cyclobutyl-carboxamide of example 47 with BBr₃ and subsequentpurification.

LCMS: m/z 500.5 (M+H)

Example 49

Trans-N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-piperazin-1-yl]ethyl]cyclohexyl]-3-methoxy-cyclobutanecarboxamide(compound 49, compound of the formula I, where R¹ istrans-3-methoxycyclobutyl, m is 2, n is 2, R²═H, R^(3a) is H, R^(3b) isH, A is CH₂, R⁴ is tert.butyl, R⁵ is isopropyl, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

LCMS: m/z 500.4 (M+H)

¹H-NMR (CDCl₃, 600 Hz): δ [ppm] 6.13 (s, 1H), 5.19 (d, 1H), 4.11 (m,1H), 3.72 (m, 1H), 3.65 (m, 4H), 3.24, (s, 3H), 2.81 (m, 2H), 2.45-2.55(m, 5H), 2.4 (m, 2H), 2.17 (m, 2H), 1.98 (m, 2H), 1.78 (m, 2H), 1.44 (m,2H), 1.33 (s, 9H), 1.2-1.28 (m, 7H), 1.08 (m, 4H).

Example 50

Trans-N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide(compound 50, compound of the formula I, where R¹ istrans-3-hydroxycyclobutyl, m is 2, n is 2, R²═H, R^(3a) is H, R^(3b) isH, A is CH₂, R⁴ is tert.butyl, R⁵ is isopropyl, and the radicalR¹—C(═O)—NH and the radical R² have trans-configuration)

The title compound was prepared by O-demethylation of the corresponding3-methoxy-cyclobutyl-carboxamide of example 49 with BBr₃ and subsequentpurification.

LCMS: m/z 486.4 (M+H)

¹H NMR (CHLOROFORM-d, 600 MHz): δ=6.14 (s, 1H), 5.2 (d, J=7.5 Hz, 1H),4.62 (m, 1H), 3.60-3.8 (broad, 4H), 2.8 (m, 2H), 2.52 (m, 2H), 2.45 (m,broad, 2H), 2.17 (m, 2H), 1.97 (m, 2H), 1.7 (m, 2H), 1.57 (m, 7H), 1.3(s, 9H), 1.2 (m, 6H), 1.1 (m, 4H).

IV. Biological Investigations 1. Receptor Binding Studies

The substance to be tested was either dissolved in methanol/Chremophor®(BASF SE) or in dimethyl sulfoxide and then diluted with water to thedesired concentration.

a) Dopamine D₃ receptor:

-   -   The assay mixture (0.250 ml) was composed of membranes derived        from ˜10⁶ HEK-293 cells possessing stably expressed human        dopamine D₃ receptors, 0.1 nM [¹²⁵I]-iodosulpride and incubation        buffer (total binding) or, in addition, test substance        (inhibition curve) or 1 μM spiperone (nonspecific binding). Each        assay mixture was run in triplicate.    -   The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM        KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM        quinolone and 0.1% ascorbic acid (prepared fresh daily). The        buffer was adjusted to pH 7.4 with HCl.        b) Dopamine D_(2L) receptor:    -   The assay mixture (1 ml) was composed of membranes from ˜10⁶        HEK-293 cells possessing stably expressed human dopamine D_(2L)        receptors (long isoform) and 0.01 nM [¹²⁵I] iodospiperone and        incubation buffer (total binding) or, in addition, test        substance (inhibition curve) or 1 μM haloperidol (nonspecific        binding). Each assay mixture was run in triplicate.    -   The incubation buffer contained 50 mM tris, 120 mM NaCl, 5 mM        KCl, 2 mM CaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The        buffer was adjusted to pH 7.4 with HCl.        c) Measurement and analysis:    -   After having been incubated at 25° C. for 60 minutes, the assay        mixtures were filtered through a Whatman GF/B glass fiber filter        under vacuum using a cell col-lecting device. The filters were        transferred to scintillation viols using a filter transfer        system. After 4 ml of Ultima Gold® (Packard) have been added,        the samples were shaken for one hour and the radioactivity was        then counted in a Beta-Counter (Packard, Tricarb 2000 or        2200CA). The cpm values were con-verted into dpm using a        standard quench series and the program belonging to the        instrument.    -   The inhibition curves were analyzed by means of iterative        nonlinear regression analysis using the Statistical Analysis        System (SAS) which is similar to the “LIGAND” program described        by Munson and Rodbard.    -   In these tests, the compounds according to the invention exhibit        very good affinities for the D₃ receptor (<100 nM, frequently        <50 nM, in particular <10 nM) and bind selectively to the D₃        receptor.    -   The results of the binding tests are given in Table 1.

TABLE 1 Compound D3 K_(i) D2/D3 1 +++ +++ 2 +++ ++ 3 +++ ++ 4 +++ ++ 5++ ++ 6 +++ +++ 7 +++ +++ 8 +++ +++ 9 +++ +++ 10 +++ +++ 11 +++ ++ 12 +++++ 13 +++ ++ 14 +++ ++ 15 +++ +++ 16 +++ ++ 17 +++ +++ 18 +++ +++ 19+++ + 20 +++ ++ 21 +++ ++ 22 ++ +++ 23 ++ +++ 24 ++ ++ 25 +++ ++ 26 +++++ 27 +++ ++ 28 +++ ++ 29 +++ + 30 +++ ++ 31 +++ ++ 32 +++ ++ 33 ++ +++34 +++ +++ 35 +++ + 36 +++ +++ 37 +++ +++ 38 +++ ++ 39 +++ +++ 41 ++++++ 42 +++ +++ 43 +++ +++ 44 +++ +++ 45 +++ +++ 46 +++ +++ 47 +++ +++ 48+++ +++ 49 +++ +++ 50 +++ +++ K_(i) (D₃): +++ <10 nM, ++ <50 nM, + <100nM K_(i) (D_(2L))/K_(i) (D₃): +++ >50, ++ >20, + >10

2. Determination of the Microsomal Half-Life

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance are preincubated together with liver microsomesfrom different species (from rat, human or other species) (0.25 mg ofmicrosomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 inmicrotiter plates at 37° C. for 5 min. The reaction is started by addingNADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots areremoved, and the reaction is immediately stopped and cooled with thesame volume of acetonitrile. The samples are frozen until analyzed. Theremaining concentration of undegraded test substance is determined byMSMS. The half-life (T1/2) is determined from the gradient of the signalof test substance/unit time plot, it being possible to calculate thehalf-life of the test substance, assuming first order kinetics, from thedecrease in the concentration of the compound with time. The microsomalclearance (mC1) is calculated from mC1=1n2/T1/2/(content of microsomalprotein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, TheSociety for Biomoleculur Screening, 2003, 453-462; Obach, DMD, 1999 vol27. N 11, 1350-1359). The results are shown in Table 2.

TABLE 2 Compound Human mCl²⁾ [μl min⁻¹ mg⁻¹] 1 + 2 + 3 + 4 ∘ 5 ∘ 6 + 7 +8 + 9 + 10 + 11 + 12 + 13 ∘ 14 ∘ 15 ∘ 16 ∘ 17 ∘ 18 + 19 + 20 + 21 + 22 +23 + 24 ∘ 25 ∘ 26 ++ 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 +37 + 38 ++ 39 ++ 40 + mCl mikrosomal clearance ²⁾++: <20 μl min⁻¹ mg⁻¹+: 20-120 μl min⁻¹ mg⁻¹ ∘: >120 μl min⁻¹ mg⁻¹

3. Blocking the hERG Channel

The binding affinity of test drugs for the hERG cardiac K⁺ channel wasdetermined by their ability to displace tritiated dofetilide (a classIII antiarrhythmic drug and potent hERG blocker) in membrane homogenatesfrom HEK-293 cells heterogeneously expressing the hERG channel. Theassay was performed as previously described G.J. Diaz et al., Journal ofPharmacological and Toxicological Methods, 50 (2004), 187-199). Forthis, drug dilutions were prepared from 10 mM DMSO stocks and thefollowing were added to a 96-well polystyrene plate (Perkin-ElmerOptiplate): 20 μl of assay binding buffer (for total bounds), or 1 μMastemizole (for non-specific bounds), or test drug, 50 μl of[³H]dofetilide (20 nM, ˜80 Ci/mmol specific activity), and 130 μl ofmembrane homogenate from HEK 293 cells stably transfected with hERG K⁺channels (final protein concentration of 30 μg per well). The plateswere incubated at ambient temperature for 45 min, aspirated onto GF/Bfilter plates (Perkin-Elmer), and washed with 2 ml of cold wash buffer.After allowing the plates to dry, 50 μl of scintillant (Per-kin-ElmerMicroScint 20) were added to each well and the radioactivity was countedin a Perkin-Elmer Topcount NXT scintillation counter. IC₅₀determinations were calculated from competition curves using 6 drugconcentrations, half-log apart, starting at a high concentration of 100μM (final assay DMSO concentration=1%) using a four-parameter logisticequation. The results are given as IC₅₀ value. The compound of example 1showed an IC₅₀ of >10 μm.

We claim:
 1. A compound of the formula I

where m is 1 or 2, n is 1 or 2, A is selected from the group consistingof CH₂, CH₂CH₂, CHFCH₂ and CF₂CH₂, R¹ is an oxygen containing cyclicradical selected from oxetanyl, fluorinated oxetanyl, oxolanyl,fluorinated oxolanyl, C₃-C₆ cycloalkyl, which carries one or two oxygencontaining radicals selected from the group consisting of OH,C₁-C₂-alkoxy, fluorinated C₁-C₂-alkoxy, and a carbonyl oxygen, and whichmay additionally carry 1 or 2 radicals selected from fluorine,C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl; R² is selected from the groupconsisting of hydrogen and fluorine, R^(3a) is selected from the groupconsisting of hydrogen and methyl, R^(3b) is selected from the groupconsisting of hydrogen and methyl, R⁴ is branched C₄-C₆ alkyl orbranched fluorinated C₄-C₆ alkyl, and R⁵ is selected from the groupconsisting of C₁-C₆ alkyl, fluorinated C₁-C₃ alkyl,C₁-C₂-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₂-alkoxy-C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, fluorinated hydroxy-C₁-C₄-alkyl, oxetanyl,fluorinated oxetanyl, oxolanyl, fluorinated oxolanyl, C₃-C₅ cycloalkyl,fluorinated C₃-C₅ cycloalkyl, C₃-C₅ cycloalkyl-C₁-C₄-alkyl, fluorinatedC₃-C₅ cycloalkyl-C₁-C₄-alkyl, C₃-C₅ cycloalkoxy-C₁-C₄-alkyl andfluorinated C₃-C₅ cycloalkoxy-C₁-C₄-alkyl, where the cycloalkyl moietyin the last six mentioned groups of radicals may carry 1 or 2 radicalsselected from hydroxyl, C₁-C₂-alkoxy, fluorinated C₁-C₂-alkoxy,C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl, where the cycloalkoxy moiety inthe last two mentioned radicals may carry 1 or 2 radicals selected fromhydroxyl, C₁-C₂-alkoxy, fluorinated C₁-C₂-alkoxy, C₁-C₂-alkyl andfluorinated C₁-C₂-alkyl, the N-oxides, the prodrugs and thepharmaceutically acceptable salts of these compounds.
 2. The compound ofclaim 1, wherein R¹ is selected from the group consisting of C₃-C₆cycloalkyl, which carries one oxygen containing radical selected fromthe group consisting of OH, methoxy, and a carbonyl oxygen, and whichmay additionally carry 1 radical selected from fluorine, C₁-C₂-alkyl andfluorinated C₁-C₂-alkyl.
 3. The compound of claim 1, wherein R¹ isselected from the group consisting of 1-hydroxycyclopropyl,2-hydroxycyclopropyl, 1-hydroxycyclobutyl, 2-hydroxycyclobutyl,3-hydroxycyclobutyl, 3-hydroxy-3-(trifluoromethyl)-cyclobutyl,2-oxocyclobutyl, 3-hydroxycyclopentyl, 2-hydroxycyclopentyl,3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl and4-oxocyclohexyl.
 4. The compound of claim 1, wherein R¹ is 2-oxetanyl or3-oxetanyl.
 5. The compound of any of the preceding claims, wherein R²is hydrogen.
 6. The compound of any of the preceding claims, wherein mis
 2. 7. The compound of any of the preceding claims, wherein n is
 2. 8.The compound of any of claims 1 to 7, wherein both m and n are
 1. 9. Thecompound of any of the preceding claims, wherein R^(3a) and R^(3b) arehydrogen.
 10. The compound of any claims 1 to 8, wherein either R^(3a)is methyl and R^(3b) is hydrogen or R^(3a) is hydrogen and R^(3b) ismethyl.
 11. The compound of any of the preceding claims, wherein A isCH₂.
 12. The compound of any of claims 1 to 10, wherein A is CH₂CH₂,CHFCH₂ or CF₂CH₂.
 13. The compound of any of the preceding claims,wherein R⁴ is branched C₄-C₆ alkyl and in particular tert.-butyl. 14.The compound of any of the preceding claims, wherein R⁵ is selected fromthe group consisting of, C₁-C₆ alkyl, fluorinated C₁-C₃ alkyl, and C₃-C₅cycloalkyl, which is unsubstituted or carries 1 or 2 radicals selectedfrom fluorine, C₁-C₂-alkyl and fluorinated C₁-C₂-alkyl.
 15. The compoundof claim 14, wherein R⁵ is selected from the group consisting ofdifluoromethyl, trifluoromethyl, isopropyl, tert.-butyl, cyclopropyl,1-methylcyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl,2,2-difluorocyclopropyl, cyclobutyl, 1-fluorocyclobutyl,3,3-difluorocyclobutyl, and cyclopentyl.
 16. The compound of any of theclaims 1 to 13, wherein R⁵ is selected from the group consisting ofC₁-C₂-alkoxy-C₁-C₂-alkyl, fluorinated C₁-C₂-alkoxy-C₁-C₂-alkyl andhydroxy-C₁-C₄-alkyl.
 17. The compound of claim 16, wherein R⁵ isselected from the group consisting of methoxymethyl, ethoxymethyl,2-methoxyethyl, difluoromethoxymethyl, 2-(difluoromethoxy)ethyl,trifluoromethoxymethyl, 2-(trifluoromethoxy)ethyl,methoxydifluoromethyl, ethoxydifluoromethyl,2-methoxy-1,1-difluoroethyl, hydroxymethyl, 2-hydroxyethyl,2-hydroxypropyl and 2-hydroxy-2-methylpropyl.
 18. The compound of any ofthe preceding claims, wherein A is CH₂, CH₂CH₂, CHFCH₂ or CF₂CH₂; R¹ is4-hydroxycyclohexyl, 3-hydroxycyclobutyl, or3-(trifluoromethyl)-3-hydroxycyclobutyl; R² is hydrogen; R^(3a) andR^(3b) are hydrogen or either R^(3a) is methyl and R^(3b) is hydrogen orR^(3a) is hydrogen and R^(3b) is methyl; and R⁴ is tert-butyl.
 19. Thecompound of any of the preceding claims, which is a compound of theformula Ia,

where R¹, R^(3a), R^(3b), R⁵ and A are as defined in any one of thepreceding claims, the N-oxides, the prodrugs and the pharmaceuticallyacceptable salts of these compounds.
 20. The compound of any of claims 1to 18, which is a compound of the formula Ic,

where R¹, R^(3a), R^(3b), R⁵ and A are as defined in any one of thepreceding claims, the N-oxides, the prodrugs and the pharmaceuticallyacceptable salts of these compounds.
 21. The compound of any of thepreceding claims, where in formulae I or Ia or Ic the radicalR¹—C(═O)—NH and the radical R² predominately adopt cis-configuration.22. The compound of any of claims 1 to 20, where formulae in I or Ia orIc the radical R¹—C(═O)—NH and the radical R² predominately adopttrans-configuration.
 23. The compounds according to claim 1, selectedfrom the group consisting of:N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;trans-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;cis-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;cis-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;N-[4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxycyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxycyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxycyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxycyclohexanecarboxamide,N-[3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-3-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,N-[3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,cis-N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,trans-N-[4-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,N-[4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-(2,6-ditert-butylpyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-methoxy-cyclohexanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,N-[cis-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,N-[trans-4-[2-[4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-3-(trifluoromethyl)cyclobutanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(1-methylcyclopropyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[(3R)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[(3S)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[(3S)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[(3S)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[(3S)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[(3S)-4-[2-tert-butyl-6-(2-methoxyethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-(2-tert-butyl-6-cyclopentyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide,N-[3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[cis-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[trans-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[cis-3-[2-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclobutyl]-3-hydroxy-cyclobutanecarboxamide,N-[4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,trans-N-[cis-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[trans-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,cis-N-[cis-4-[2-[4-[2-tert-butyl-6-(methoxymethyl)pyrimidin-4-yl]piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide,and the N-oxides, the prodrugs and the pharmaceutically acceptable saltsof these compounds.
 24. The compound according to claim 1, selected fromthe group consisting ofTrans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide;N-[3-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclobutyl]-trans-4-hydroxy-cyclohexanecarboxamide;Cis-N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide;Cis-N-[4-[2-[(3S)-4-[2-tert-butyl-6-(difluoromethyl)pyrimidin-4-yl]-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-trans-4-hydroxy-cyclohexanecarboxamide;and the N-oxides, the prodrugs and the pharmaceutically acceptable saltsof these compounds
 25. The compound according to claim 1, selected fromthe group consisting oftrans-N-[(1S)-3-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclopentyl]-4-hydroxy-cyclohexanecarboxamide;trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-4-hydroxy-cyclohexanecarboxamide;trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-3-methoxy-cyclobutanecarboxamide;trans-N-[4-[2-[(3S)-4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-3-methyl-piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide;trans-N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-piperazin-1-yl]ethyl]cyclohexyl]-3-methoxy-cyclobutanecarboxamide;trans-N-[4-[2-[4-(2-tert-butyl-6-isopropyl-pyrimidin-4-yl)-piperazin-1-yl]ethyl]cyclohexyl]-3-hydroxy-cyclobutanecarboxamide;and the N-oxides, the prodrugs and the pharmaceutically acceptable saltsof these compounds
 26. A compound of any of claims 1 to 25 for the useas a medicament.
 27. A pharmaceutical composition comprising at leastone compound as claimed in any of claims 1 to 25, optionally togetherwith at least one physiologically acceptable carrier or auxiliarysubstance.
 28. A method for treating a medical disorder or conditionsusceptible to treatment with a dopamine D₃ receptor ligand, said methodcomprising administering an effective amount of at least one compound asclaimed in any of claims 1 to 25 to a subject in need thereof.
 29. Themethod of claim 28, wherein the medical disorder is a disorder orcondition of the central nervous system.
 30. The method of claim 28,wherein the medical disorder is a disorder or condition selected fromthe group of Parkinson's disease, schizophrenia, bipolar disorder,depression, motivation disturbances, anxiety, dyskinesia, in particularL-DOPA induced dyskinesia (LID), cognitive dysfunction, pain, disorderassociated with drug abuse, and eating disorders.
 31. The method ofclaim 28, wherein the medical disorder is renal function disorders, suchas diabetic nephropathy.